Organocatalytic asymmetric synthesis of N,N-bis(dihydrofuranyl) hydroxyamines: A cascade reaction involving friedelcrafts alkylation, internal redox reaction umpolung

Article abstract of DOI:10.1246/cl.2011.843

Stereoselective syntheses of N,N-bis(dihydrofuranyl)- hydroxyamines from phenols and nitroolefins have been accomplished by means of cycle-specific catalysis with guanidine/bisthiourea organocatalyst and achiral base. Circumstantial evidence supports the idea that a nitroso intermediate participates in the dimerization, which involves internal redox reaction/umpolung.

Full text of DOI:10.1246/cl.2011.843

doi:10.1246/cl.2011.843
Published on the web July 16, 2011
843
Organocatalytic Asymmetric Synthesis of N,N-Bis(dihydrofuranyl)hydroxyamines:
A Cascade Reaction Involving Friedel-Crafts Alkylation,
Internal Redox Reaction, and Umpolung
Yoshihiro Sohtome,*,³ Takahisa Yamaguchi, Bongki Shin, and Kazuo Nagasawa*
Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-858
(Received May 31, 2011; CL-110461; E-mail: sohtome@riken.jp, knaga@cc.tuat.ac.jp)
Stereoselective syntheses of N,N-bis(dihydrofuranyl)-
hydroxyamines from phenols and nitroolefins have been
accomplished by means of cycle-specific catalysis with
guanidine/bisthiourea organocatalyst and achiral base. Circum-
stantial evidence supports the idea that a nitroso intermediate
participates in the dimerization, which involves internal redox
reaction/umpolung.
of the multiple reactive sites.9,10,14 For example, Chen and co-
workers reported that cinchona-based thiourea organocatalysts
promote the chemo- and regioselective Friedel-Crafts (FC)
reaction of naphthols with nitroolefins 3 to afford the FC adducts
4 with 85-95% ee, but the dimeric dihydronaphthofurans 5 are
also concomitantly formed. In contrast, we have successfully
developed a catalytic system using 1,3-diamine-tethered guani-
dine/bisthiourea organocatalyst 1 that enables selective access
to 4 (66-99% yield with 82-94% ee) with the generation of only
a trace amount of dimer 5.10 These results suggest that the
conformationally flexible organocatalyst 1 can effectively dis-
sociate from the FC adduct 4 after the bond-forming reaction
takes place in the FC reaction, thereby suppressing the
conversion of 4 to the dimer 5.
Encouraged by these findings, we were inspired to examine
the use of 1 to mediate the asymmetric cycle-specific cascade
assembly of N,N-bis(dihydrofuranyl)hydroxyamines 5 from
phenols 2 and nitroolefins 3. We postulated that if the catalyst
1 or FC adducts 4 could be appropriately stimulated after the
complete conversion of 2 to 4, dimer formation should
effectively take place. After extensive screening,15,16 we were
pleased to find that addition of potassium carbonate (50 mol %)
after the completion of the 1-catalyzed FC reaction is effective to
promote the dimer-forming reaction of 4, giving the correspond-
ing (dihydrofuranyl)hydroxyamines 5 in a single-flask operation
(Table 1).17 Both aromatic (Entries 1-3) and aliphatic substitu-
ents (Entry 4) as the R group in 4 are available in the present
system, giving the corresponding dimeric dihydrofurans 5
in 76-99% yield with 5:1 ¼ 20:1 dr, 90-99% ee. Electron-
enriched phenols such as 4ba gave the dimeric product 5ba with
10:1 dr and 95% ee, although there is still room to improve the
reactivity.
An understanding of the mechanism of this unusual
dimerization (4 to 5) is of principal importance for further
development of this unique cascade. To gain insight into the
roles of the guanidine/bisthiourea organocatalyst 1 and potas-
sium carbonate in the dimer-forming reaction, we utilized
(S)-4aa (88% ee),10 which was isolated by silica gel column
chromatography, as a reaction substrate (Table 2). The cooper-
ative procedure using 1 and potassium carbonate exhibited
similar reactivity and selectivities to the single-flask procedure
described in Table 1, Entry 1. In contrast, a significant decline
of the reactivity was observed in the absence of 1, resulting in
lower conversion (34%) and recovery of (S)-4aa (65%). It is also
important to note that the enantiomeric excess values of both the
(S,S)-5aa and the recovered-(S)-4aa were apparently maintained
in the absence of 1. These results suggest that the catalyst and
potassium carbonate cooperatively govern both the reaction rate
The sequence of multiple catalytic asymmetric reactions is
one of the most powerful synthetic tactics to attain a rapid
increase of molecular complexity.1 Among the methods avail-
able, cycle-specific catalysis, which allows discrete control of
individual bond-forming processes by utilizing distinct catalysts,
has received much attention, because the strategy enables
flexible access to a range of products, depending on the catalytic
system used.2 Such chiral-catalyst-based methodologies should
effectively increase the stereochemical diversity of products that
can be constructed with small molecules.3 Here, we present our
studies on the development of cycle-specific catalysis with the
combination of guanidine/bisthiourea 14-8 and an external
achiral base, focusing on the synthesis of N,N-bis(dihydro-
furanyl)hydroxyamines 5 from phenols 2 and nitroolefins 3
(Scheme 1).9,10 The mechanism of the dimerization (4 to 5),
which involves umpolung11 and internal redox reaction12,13 is
also discussed.
Phenolates are potentially attractive nucleophiles for the
design of cycle-specific cascade reactions, because multiple
reactive sites are available in the aromatic moiety (i.e., ortho-
and para-positions), in addition to the oxygen function.
Although several examples of catalytic asymmetric reaction of
phenolates have recently been reported, methodologies that can
selectively access both 4 and 5 using phenolates have not been
reported, likely due to the difficulty in controlling the reactivity
Ar = 3,5-(CF3)2C6H3
S
i-Pr
N
i-Pr
S
X
Ar
Ar
R
N
N
N
N
N
N
OH
N
R
H
H
H
H
H
1) guanidine/bisthiourea 1
X
NO2
O
O
R
OH
2) external base
X
2
3
5
R
NO2
1
+
1
X
base
OH
4
dimerization
FC reaction
(previous work)
(this work)
Scheme 1. Synthesis of 5 by utilizing cycle-specific catalysis.
Chem. Lett. 2011, 40, 843-845
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

844
O
N
Table 1. Some examples of the cascade reaction using 1 for the
preparation of (S,S)-5a,b
R
R
S
NO2
S
S
X
OH
N
R
R
R
O
K2CO3
OH
NO2
S
(S,S)-I
(50 mol%)
X
2
+
3
1 (5 mol%)
(S)-4
S
S
meso-5
+
X
O
O
toluene
OH
(S)-4
OH
step iii
step i
X
X
(S,S)-5
O
N
O
N
R
R
1.
2.
step ii
OH
N
O
OH
OH
N
X
X
6
OH
7
O
O
O
O
O
Scheme 2. Working hypothesis for the generation of (S,S)-I.
(2a + 3a) 5aa
20 °C, 12 h
(2a + 3b) 5ab
20 °C, 24 h
99% yield,c dr 7:1,d 99% eee
99% yield,c dr 5:1,d 90% eee
OH
1 (5 mol%)
K2CO3 (50 mol%)
Ph
O
N
3.
4.f
(S,S)-5aa
meso-5aa
N
S
Et
S
Et
S
(S)-4aa
S
Ph
OH
N
OH
Ph
toluene
(0.025 M)
rt, 24 h
O
N
88% ee
8
(S,S)-9aa
(1.0 equiv)
O
O
O
O
(S,S)-5aa: 31% yielda
(S,S): meso = 8:1 drb
99% eec
46% yielda
anti:syn >20:1b
99% eec
(2a + 3c) 5ac
20 °C, 28 h
(2a + 3d) 5ad
20 °C, 43 h
91% yield,c dr 6:1,d 93% eee
76% yield,g dr >20:1,d 99% eee
Scheme 3. The reaction of 8 with (S)-4aa. aNMR yield.
5.
1
c
bDetermined by H NMR. Determined by chiral HPLC.
OH
N
O
O
Another intriguing question concerns the unusual chemo-
type of the nitro group of 418 in the transformation from 4 to 5,
which formally involves reversal of the inherent polarity in the
nitro group (phenoxide anion attacks the ¡-position to the nitro
group)11 and internal redox reaction (oxidation at the ¡-position
O
O
O
O
(2b + 3a) 5ba
20 °C, 24 h
51% yield,g dr 10:1,d 95% eee
aCompounds (S)-4 were prepared using the conditions reported
in ref. 10a. bPotassium carbonate was added after verifying
complete conversion of 2 to 4 in the 1-catalyzed FC
to the nitro group and reduction of the nitro group).12,13
A
mechanism that can well explain these umpolung/redox
processes is in situ generation of the highly reactive aliphatic
nitroso species (S,S)-I. We hypothesized that the intramolecular
nucleophilic addition of phenolate to the ¡-position of nitronate
(Scheme 2, step iii) might take place in an anti-selective manner
due to the steric repulsion of the R group in 7, leading to
generation of (S,S)-I.19
These speculations stimulated us to examine the reaction
of nitrosobenzene (8) with the isolated (S)-4aa (88% ee). We
anticipated that nitroso-aldol reaction and subsequent elimina-
tion of the nitro group would lead to the construction of another
dihydrofuran moiety.20 As can be seen in Scheme 3, the highly
diastereo- and enantioselective heterocoupling reaction of 8 with
(S)-4aa took place both with catalyst 1, giving the corresponding
(dihydrofuranyl)hydroxyamine (S,S)-9aa with the concomitant
generation of (S,S)-5aa.21 Thus, the investigation using 8
provided circumstantial evidence in support of the idea that
the nitroso species participates as an intermediate in the
dimerization. It is also important to note that the results shown
in Scheme 3 indicate that mono(dihydrofuranyl)hydroxyamine
could be constructed by designing the reaction of (S)-4 with
suitable electrophiles.
reaction.10a cIsolated yield. Determined by H NMR. Deter-
d
1
e
mined by chiral HPLC. f10 mol % of 1 was used. gNMR yield.
Table 2. The reaction of (S)-4aa in the presence and absence
of 1
Ph
OH
N
Ph
Ph
K2CO3
(50 mol%)
S
NO2
S
S
+ meso-5aa
O
O
toluene
20 °C, 12 h
OH
(S)-4aa :88% ee
(S,S)-5aa
(S,S)-5aa
drb
/% (S,S):meso (S,S)-5aac
(S)-4aa
Recoverya eec
Yielda
ee
Entry Catalyst 1
/%
/%
1
2
5 mol %
none
99
34
8:1
>20:1
1
98
87
c
n.d.d
65
n.d.d
89
aNMR yield. Determined by H NMR. Determined by chiral
b
d
HPLC. Not determined.
and the stereoselection in the dimer-forming processes. Thus,
we concluded that 1) the guanidine/bisthiourea 1 selectively
promotes the chemo-, regio-, and enantioselective 1,4-type FC
alkylation of 2 with 3 to produce 4, and 2) the subsequent
addition of potassium carbonate results in cooperative activation
of the FC product 4 together with guanidine/bisthiourea 1,
facilitating the formation of the N,N-bis(dihydrofuranyl)-
hydroxyamines 5.
In summary, we have explored a new cycle-specific
catalysis by exploiting the combination of guanidine/bisthiourea
1 and potassium carbonate. Our findings show that organo-
catalyst 1 can effectively control the reactivity and selectivity
of phenolates, enabling selective access to both chiral phenols 4
and N,N-bis(dihydrofuranyl)hydroxyamines 5 simply by alter-
nating the reaction conditions. Further applications of cycle-
specific catalysis utilizing the conformationally flexible organo-
Chem. Lett. 2011, 40, 843-845
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

845
catalysts to other types of cascade reactions are under exami-
nation.
of their mechanistic studies, see: b) R. R. Knowles, E. N.
Jacobsen, Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678.
For Takemoto’s original work, see: a) T. Okino, Y. Hoashi, Y.
Takemoto, J. Am. Chem. Soc. 2003, 125, 12672. Other work
by Takemoto and co-workers, see ref. 4, as well as their
review: b) Y. Takemoto, Chem. Pharm. Bull. 2010, 58, 593.
T.-Y. Liu, H.-L. Cui, Q. Chai, J. Long, B.-J. Li, Y. Wu, L.-S.
Ding, Y.-C. Chen, Chem. Commun. 2007, 2228.
8
9
This work was supported by Grant-in-Aid for Young
Scientist (B) and a grant from The Uehara Memorial Founda-
tion. B. S. is grateful for a Sasagawa Scientific Research Grant.
References and Notes
³
Present address: RIKEN Advanced Science Institute, 2-1
Hirosawa, Wako, Saitama 351-0198
10 a) Y. Sohtome, B. Shin, N. Horitsugi, R. Takagi, K. Noguchi,
K. Nagasawa, Angew. Chem., Int. Ed. 2010, 49, 7299. b) Y.
Sohtome, B. Shin, N. Horitsugi, K. Noguchi, K. Nagasawa,
Chem.®Asian J., in press.
1
Selected recent reviews on organocatalytic cascade reac-
tions: a) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010,
2, 167. b) A. M. Walji, D. W. C. MacMillan, Synlett 2007,
1477. c) C. J. Chapman, C. G. Frost, Synthesis 2007, 1. d) X.
Yu, W. Wang, Org. Biomol. Chem. 2008, 6, 2037.
11 For a general review on umpolung reactions, see: D.
Seebach, Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
12 For a review on internal redox reactions, see: N. Z. Burns,
P. S. Baran, R. W. Hoffmann, Angew. Chem., Int. Ed. 2009,
48, 2854.
2
Selected reviews on cycle-specific organocatalysis utilizing
two distinct catalysts: a) J. Zhou, Chem.®Asian J. 2010, 5,
422. b) L. M. Ambrosini, T. H. Lambert, ChemCatChem
2010, 2, 1373. For recent selected examples, see: c) Y.
Huang, A. M. Walji, C. H. Larsen, D. W. C. MacMillan,
J. Am. Chem. Soc. 2005, 127, 15051. d) J. Zhou, B. List,
J. Am. Chem. Soc. 2007, 129, 7498. e) W. Schrader, P. P.
Handayani, J. Zhou, B. List, Angew. Chem., Int. Ed. 2009,
48, 1463. f) B. Simmons, A. M. Walji, D. W. C. MacMillan,
Angew. Chem., Int. Ed. 2009, 48, 4349. g) H. Jiang, P.
Elsner, K. L. Jensen, A. Falcicchio, V. Marcos, K. A.
Jørgensen, Angew. Chem., Int. Ed. 2009, 48, 6844. h) Y.-G.
Wang, T. Kumano, T. Kano, K. Maruoka, Org. Lett. 2009,
11, 2027. i) S. T. Scroggins, Y. Chi, J. M. J. Fréchet, Angew.
Chem., Int. Ed. 2010, 49, 2393. j) S. P. Lathrop, T. Rovis,
J. Am. Chem. Soc. 2009, 131, 13628. k) C. M. Filloux, S. P.
Lathrop, T. Rovis, Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20666.
13 For selected examples of organocatalytic asymmetric inter-
nal redox reactions, see: a) N. T. Reynolds, J. R. de Alaniz, T.
Rovis, J. Am. Chem. Soc. 2004, 126, 9518. b) K. Y.-K. Chow,
J. W. Bode, J. Am. Chem. Soc. 2004, 126, 8126. c) S. S.
Sohn, E. L. Rosen, J. W. Bode, J. Am. Chem. Soc. 2004, 126,
14370. d) Y. K. Kang, S. M. Kim, D. Y. Kim, J. Am. Chem.
Soc. 2010, 132, 11847. e) K. Mori, K. Ehara, K. Kurihara, T.
Akiyama, J. Am. Chem. Soc. 2011, 133, 6166.
14 Following the work reported by Chen and co-workers,9
C-alkylation/O-cyclization organocascade reactions have
been reported, see: a) X.-S. Wang, G.-S. Yang, G. Zhao,
Tetrahedron: Asymmetry 2008, 19, 709. b) X.-S. Wang,
C.-W. Zheng, S.-L. Zhao, Z. Chai, G. Zhao, G.-S. Yang,
Tetrahedron: Asymmetry 2008, 19, 2699. c) L. Hong, L.
Wang, W. Sun, K. Wong, R. Wang, J. Org. Chem. 2009, 74,
6881.
3
4
For a review, see: M. D. Burke, S. L. Schreiber, Angew.
Chem., Int. Ed. 2004, 43, 46.
15 Our initial attempts to promote the dimer-formation by
alternating the reaction solvent, aiming for the conforma-
tional change of 1, failed. Only trace amounts of 5 were
obtained in all the solvents tested.
Selected recent reviews on asymmetric H-bond donor
catalysis: a) Hydrogen Bonding in Organic Synthesis, ed.
by P. M. Pihko, Wiley-VCH, 2009. b) Z. Zhang, P. R.
Schreiner, Chem. Soc. Rev. 2009, 38, 1187. c) A. G. Doyle,
E. N. Jacobsen, Chem. Rev. 2007, 107, 5713. d) S. J.
Connon, Chem.®Eur. J. 2006, 12, 5418. e) M. S. Taylor,
E. N. Jacobsen, Angew. Chem., Int. Ed. 2006, 45, 1520.
For our first report of the development of guanidine/
bisthiourea organocatalysts, see: a) Y. Sohtome, Y.
Hashimoto, K. Nagasawa, Adv. Synth. Catal. 2005, 347,
1643. For our personal account: b) Y. Sohtome, K.
Nagasawa, Synlett 2010, 1.
Selected recent reviews on guanidine and guanidinium
organocatalysts: a) X. Fu, C.-H. Tan, Chem. Commun. 2011,
in press. doi:10.1039/c0cc03691a. b) M. Terada, J. Synth.
Org. Chem., Jpn. 2010, 68, 1159. c) D. Leow, C.-H. Tan,
Synlett 2010, 1589. d) Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related Organo-
catalysts, ed. by T. Ishikawa, Wiley, 2009. e) D. Leow, C.-H.
Tan, Chem.®Asian J. 2009, 4, 488. f) T. Ishikawa, T.
Kumamoto, Synthesis 2006, 737.
16 See Supporting Information.22
17 In general, the ee values of (S)-5 are higher than those of (S)-
4; 5aa (99% ee) vs. 4aa (88% ee), 5ab (99% ee) vs. 4ab
(84% ee), 5ac (93% ee) vs. 4ac (84% ee), 5ad (99% ee) vs.
4ad (93% ee), and 5ba (95% ee) vs. 4ba (91% ee). Thus, the
rate of the heterocoupling reaction of major (S)-4 and minor
enantiomer (R)-4, in which meso-5 is generated, appears to
proceed more rapidly than the homocoupling reaction to
afford (S,S)-5, thereby increasing the ee value of (S,S)-5 in
the dimerization processes.
18 For a review, see: N. Ono, The Nitro Group in Organic
Synthesis, Wiley-VCH, New York, 2001.
19 A reversal of the sense of the reactivity of nitronate, in the
case of a pyridine group proximate to a nitro group, has been
reported: H. E. Zimmerman, P. Wang, Helv. Chim. Acta
2001, 84, 1342.
5
6
20 For a recent example of elimination of the nitro group, see:
D. Kundu, M. Samim, A. Majee, A. Hajra, Chem. Asian J.
2011, 6, 406, and references cited therein.
7
For pioneering work utilizing chiral urea/thiourea catalysts
by Jacobsen’s group, see: a) M. S. Sigman, E. N. Jacobsen,
J. Am. Chem. Soc. 1998, 120, 4901. Other work by Jacobsen
and co-workers, see ref. 4; For a comprehensive discussion
21 For mechanistic discussion, see Supporting Information.22
22 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 843-845
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/