Diastereo- and enantioselective Aza-MBH-type reaction of nitroalkenes to N-tosylimines catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1021/ol9011458

The first example of diastereo- and enantioselective aza-MBH-type reaction was accomplished by the asymmetric synthesis of β-nitro-γenamines via a (1R,2R)-diaminocyclohexane thiourea derivative mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) and high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1:99 dr).

Full text of DOI:10.1021/ol9011458

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3310-3313
Diastereo- and Enantioselective
Aza-MBH-Type Reaction of Nitroalkenes
to N-Tosylimines Catalyzed by
Bifunctional Organocatalysts
Xiao Wang, Yong-Fei Chen, Liang-Feng Niu, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou UniVersity, Lanzhou 730000, P. R. China
xupf@lzu.edu.cn
Received May 23, 2009
ABSTRACT
The first example of diastereo- and enantioselective aza-MBH-type reaction was accomplished by the asymmetric synthesis of ꢀ-nitro-γ-
enamines via a (1R,2R)-diaminocyclohexane thiourea derivative mediated tandem Michael addition and aza-Henry reaction in good yields (up
to 95%) and high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1:99 dr).
Reactions that involve the formation of C-C bonds are
considered as the most important processes in organic
synthesis. Tandem reactions that involve the production
of multiple stereogenic centers in a single manipulation
serve as a powerful tool for the rapid and efficient
assembly of complex structures from simple starting
materials with minimal production of waste.1 Development
of catalytic tandem reactions has proven to be a chal-
lenging task. The coupling of activated alkenes (vinyl
anion equivalents) with various carbon electrophiles
mediated by a tertiary amine or tertiary phosphine,
commonly known as the Morita-Baylis-Hillman (MBH)
reaction, has emerged as an important tandem C-C bond-
forming reaction in organic synthesis.2-4
receptors promoted by chiral secondary amines.5 However,
a significant unmet challenge in this area still remains, such
as diastereo- and enantioselective aza-MBH-type reactions
using direct organocatalytic methods. A variety of activated
alkenes have been employed as substrates in the MBH
reaction for more than three decades,2 but an olefin activated
by a nitro group has been employed only recently.5,6 As for
the electrophiles, activated imines are the most sought-after
(2) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 2815. (b) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. DE 2155113,
1972; Chem. Abstr. 1972, 77, 434174. (c) Hillman, M. E. D.; Baylis, A. B.
U.S. Patent 3743669, 1973.
(3) For recent reviews on MBH reaction: (a) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811. (b) Kataoka, T.; Kinoshita,
H. Eur. J. Org. Chem. 2005, 45. (c) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614. For recent reviews on the aza-
MBH reaction: (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 18, 2905.
(4) For recent mechanism studies: (a) Aggarwal, V. K.; Fulford, S. Y.;
Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706. (b) Santos,
L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N. Angew.
Chem., Int. Ed. 2004, 43, 4330. (c) Price, K. E.; Broadwater, S. J.; Walker,
B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980.
Recently Shi and co-workers described an enantioselective
intermolecular cross-double addition between two Michael
(1) For recent reviews of tandem reactions, see: (a) Guo, H.-C.; Ma,
J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. (b) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Pellissier,
H. Tetrahedron 2006, 62, 2143. (d) Tietze, L. F.; Rackelmann, N. Pure
Appl. Chem. 2004, 76, 1967. (e) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551.
(5) (a) Sun, X. H.; Sengupta, S.; Petersen, J. L.; Wang, H.; Lewis, J. P.;
Shi, X. D. Org. Lett. 2007, 9, 4495. (b) Zhong, C.; Chen, Y. F.; Petersen,
J. L.; Akhmedov, N. G.; Shi, X. D. Angew. Chem., Int. Ed. 2009, 48, 1.
10.1021/ol9011458 CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

Scheme 1. Possible Reaction Mechanism
ones for the MBH reaction, besides aldehydes, by virtue of
their electrophilicity and ability to provide aminoalkylated
activated alkenes with new chiral centers.7 However, to the
best of our knowledge, the research on the coupling of
activated imines and nitro activated olefins is very rare,6e
and stereoselective synthesis in this coupling has not been
reported.
We envisioned that the activated imines might react with
nitroalkene 1 in the presence of an easily accessible chiral
organic catalyst to afford aza-MBH-type reaction products.
The resulting ꢀ-nitro-γ-enamines are important starting
materials for diversity-oriented organic synthesis of biologi-
cally active compounds, which can be either oxidized to
R-nitro-ꢀ-amino carbonyl compounds or reduced to 2,
3-diamino alkenes.8,9
reaction.10 In our designed tandem reaction, thiourea catalyst
could first attack the nitroalkene by the tertiary amino group
and also activate the imines via hydrogen-bonding. Our
investigation began with the reaction of nitroalkene 1 with
N-Boc imine 2A catalyzed by quinine thiourea derivative
(8, 20 mol %) in toluene at -20 °C (Table 1, entry 1), which
afforded the desired product 3A in 90% yield with high
diastereoselectivity (dr 9:91) and low enantioselectivity (35%
ee). Reaction at lower temperature provided an improved
enantioselectivity (Table 1, entry 2). However, further
lowering of the reaction temperature caused low reactivity
(Table 1, entry 3). On the other hand, use of N-tosylimine
2B, under the best reaction conditions for N-Boc imine 2A,
gave the product 3B with a moderate enantioselectivity
(Table 1, entry 4).
The reaction involves a sequence of Michael addition,
aza-Henry reaction, and ꢀ-elimination. A reversible
conjugated addition of the nucleophilic catalyst to ni-
troalkene 1 generates an intermediate (step 1), which can
intercept the imine 2 to afford the second intermediate 4
(step 2). A proton shift (step 3) followed by ꢀ-elimination
gives the final product 3 with concurrent regeneration of
the catalyst (step 4) (Scheme 1).
Encouraged by this result, we performed catalyst
screenings with various chiral thioureas (Table 1, entries
5-9). It was found that all of the catalysts could catalyze
the reaction to furnish the desired product. The reaction
in the presence of (1R,2R)-diaminocyclohexane thiourea
derivative 12 gave good diastereoselectivity and enanti-
oselectivity, and (1S,2S)-diaminocyclohexane thiourea
derivatives 13 gave the opposite and moderate diastereo-
selectivity and enantioselectivity. In addition, the results
revealed that substituents in the aromatic ring of (1R,2R)-
diaminocyclohexane thiourea derivatives had a significant
effect on the diastereoselectivity and enantioselectivity but
only marginally affected the reaction rate (Table 1, entries
6-8). In contrast, replacing the 3,5-bis(trifluorometh-
Several groups reported that thiourea derivatives with
tertiary amino groups could act as bifunctional organocata-
lysts in enantioselective Michael addition and aza-Henry
(6) (a) Rastogi, N.; Namboothiri, I. N. N.; Cojocaru, M. Tetrahedron
Lett. 2004, 45, 4745. (b) Dadwal, M.; Mohan, R.; Panda, D.; Mobin, S. M.;
Namboothiri, I. N. Chem. Commun. 2006, 338. (c) Deb, I.; Dadwal, M.;
Mobin, S. M.; Namboothiri, I. N. Org. Lett. 2006, 8, 1201. (d) Dadwal,
M.; Mobin, S. M.; Namboothiri, I. N. Org. Biomol. Chem. 2006, 4, 2525.
(e) Rastogi, N.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N.
Org. Biomol. Chem. 2006, 4, 3211.
(10) For recent reviews on hydrogen bond-facilitated organocatalysis:
(a) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (b) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (c) Connon,
S. J. Chem.sEur. J. 2006, 12, 5418. (d) Connon, S. J. Chem. Commun.
2008, 2499. For recent works on hydrogen bond-facilitated organocatalysis:
(e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119. (f) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I. J. Am.
Chem. Soc. 2006, 128, 13151. (g) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. For recent works on MBH reaction catalyzed
by thiourea: (h) Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.;
Nagasawa, K. Tetrahedron 2008, 64, 9423.
(7) For recent reviews on the nucleophilic addition to imines and related
CdN systems: (a) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr.
Org. Chem. 2005, 9, 1315. (b) Weinreb, S. M.; Orr, R. K. Synthesis 2005,
1205. (c) Pihko, P. M. Lett. Org. Chem. 2005, 2, 398.
(8) Reviews on the Nef reaction: (a) Pinnick, H. W. Org. React. 1990,
38, 655. (b) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017
.
(9) For the synthesis of fine chemicals from nitroalkanes: Ballini, R.;
Palmieri, A.; Righi, P. Tetrahedron 2007, 63, 12099
Org. Lett., Vol. 11, No. 15, 2009
.
3311

Table 1. Screening of the Reaction Conditions
entry
PG
catalyst
solvent
temp (°C)
time (h)a
yield (%)b
anti:sync
ee % (syn)d
1
2
3
4
5
6
7
8
Boc
Boc
Boc
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
8
8
8
8
9
10
11
12
13
12
12
12
12
12
12
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
-20
-40
-50
-40
-40
-40
-40
-40
-40
-40
-40
-40
-40
-40
-40
5
77
72
28
25
24
24
22
24
25
48
45
55
21
30
90
75
trace
73
80
77
75
82
83
85
90
91
67
78
75
9:91
7:93
nd
35
49
nd
65
80
61
68
86
80e
87
91
91
65
10
50
17:83
13:87
35:65
27:73
11:89
67:33
10:90
4:96
9
10
11
12
13
14
15
xylene
m-xylene
MeCN
DMF
3:97
31:69
43:57
37:63
MeOH
a Reaction time was determined by TLC. b Yield of isolated product after chromatography. c Diastereomeric ratio was determined by 1H NMR. d Enantiomeric
excess was determined by HPLC. e Enantiomeric excess of anti isomer.
yl)phenyl group with other aryl groups decreased the
enantioselectivities as a result of weak hydrogen-bonding
abilities.
Other solvents were examined with 12 as a catalyst. As
expected, polar solvents (MeCN, DMF, MeOH) decreased
the activity of 12 and resulted in lower yields of 3B (Table
1, entries 13-15). In contrast, 12 in nonpolar solvents
(CH2Cl2, xylene) efficiently promoted the reaction in high
yields of 3B with good enantioselectivities (Table 1, entries
10-12).
Then we examined the scope of the reaction under the
optimized conditions. Results obtained in the addition of
nitroalkene 1 to a variety of N-tosyl imines 2a-n are
summarized in Table 2. All of the reactions were conducted
in m-xylene at -40 °C in the presence of 12 as a catalyst.
Good enantioselectivities (87-91% ee) were obtained for
aryl imines with electron-rich groups (Table 2, entries 2, 5,
6, 11, and 13), whereas electron-deficient groups decreased
the enantioselectivities (72-77% ee) (Table 2, entries 3, 4,
7-10, and 12). Reaction of n-propyl imine with 1 also
yielded the desired product 3n with good enantioselectivity
(84% ee) (Table 2, entry 14). The absolute and relative
configurations were unambiguously confirmed through X-ray
crystal structure analysis of the compound 3g11 (see Sup-
porting Information).
To study the reaction mechanism, a series of experi-
ments were performed. No reaction was observed when
nitroalkene 6 and imine 2B were used as starting materials,
which indicated ꢀ-methyl played an important role for this
reaction. To further probe the proton shift process,
deuterium-labeled nitroalkene 7 was subjected to the
reaction conditions. Although the substrate was found to
be less reactive as a result of steric effect, some products
(11) The structure of the compound 3g was determined by X-ray
analysis. CCDC-716780 contains 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.
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Org. Lett., Vol. 11, No. 15, 2009

Table 2. Reaction Substrate Scope
Scheme 2. Study of the Reaction Mechanism
In summary, we have developed an enantioselective
synthetic method via a (1R,2R)-diaminocyclohexane thio-
urea derivative mediated aza-MBH-type reaction/tandem
Michael addition and aza-Henry reaction, in which easily
prepared N-tosylimines and nitroalkene are employed as
the starting materials. This strategy provides an easy
access to structurally diverse ꢀ-nitro-γ-enamines. It is a
noteworthy advantage of the organocatalyst that the new
C-C bond formation proceeds efficiently with excellent
diastereo- and enantioselectivity.
a Reaction time was determined by TLC. b Yield of isolated product
after chromatography. c Diastereomeric ratio was determined by 1H NMR.
d Enantiomeric excess was determined by HPLC.
Acknowledgment. We are grateful for the financial
support of project 973 (2009CB626604) from the MOST,
NSFC (20772051), the Program 111 from the MOE of the
People’s Republic of China.
were isolated and the percentages of deuterium label on
the terminal protons of the olefin and the proton within
the amino group were 84-87% and 70-75%, respectively
(Scheme 2). The results suggested that there was an
intramolecular proton shift in the reaction. When nitroalk-
enes 6 were used, the reaction should be a normal MBH
pathway (Scheme 1), but at low temperature intermolecu-
lar proton shift became more difficult and in the presence
of ꢀ-methyl, it offered an intramolecular proton shift route
that is easier than intermolecular.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR and HRMS data for products
3 and X-ray crystal data in CIF format for 3g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9011458
Org. Lett., Vol. 11, No. 15, 2009
3313