Enantioselective organocatalytic three-component petasis reaction among salicylaldehydes, amines, and organoboronic acids

Article abstract of DOI:10.1021/ol203109a

The catalytic enantioselective three-component Petasis reaction among salicylaldehydes, amines, and organoboronic acids with a newly designed thiourea-binol catalyst is presented. A broad range of alkylaminophenols can be obtained in good yield (up to 92%

Full text of DOI:10.1021/ol203109a

ORGANIC
LETTERS
2012
Vol. 14, No. 4
976–979
Enantioselective Organocatalytic Three-
Component Petasis Reaction among
Salicylaldehydes, Amines, and
Organoboronic Acids
Wen-Yong Han,†,§ Zhi-Jun Wu,‡ Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China, Chengdu Institute of
Biology, Chinese Academy of Sciences, Chengdu 610041, China, and Graduate School of
Chinese Academy of Sciences, Beijing, 100049, China
yuanwc@cioc.ac.cn
Received November 20, 2011
ABSTRACT
The catalytic enantioselective three-component Petasis reaction among salicylaldehydes, amines, and organoboronic acids with a newly
designed thiourea-binol catalyst is presented. A broad range of alkylaminophenols can be obtained in good yield (up to 92%) and good to high
enantioselectivity (up to 95% ee). A possible reaction pathway for this catalytic enantioselective Petasis reaction is tentatively proposed.
As a multicomponent reaction,1 the Petasis reaction enjoys
a history of nearly two decades and makes a significant
contribution to the preparation of an assortment of com-
pounds depending on the nature of the aldehyde com-
ponent involved.2 Among them, R-amino acids starting from
glyoxylic acid and derivatives, R-hydroxyl amines starting
from glycolaldehyde and derivatives, and alkylaminophenols
starting from salicylaldehyde and derivatives are the most
easily accessible.3 In particular, studies on asymmetric induc-
tion by using various chiral reactants have achieved remark-
able success in this area.2b,2d,4 However, to date, there are only
three examples concerning the catalytic enantioselective Pet-
asis reaction reported by Takemoto5 and Schaus,6 respectively
(Scheme 1, eqs 1À3). Notably, the three existing catalytic
(4) For selected examples, see: (a) Muncipinto, G.; Moquist, P. N.;
Schreiber, S. L.; Schaus, S. E. Angew. Chem., Int. Ed. 2011, 50, 8172. (b)
Churches, Q. I.; White, J. M.; Hutton, C. A. Org. Lett. 2011, 13, 2900. (c)
Churches, Q. I.; Johnson, J. K.; Fifer, N. L.; Hutton, C. A. Aust. J. Chem.
2011, 64, 62. (d) Hong, Z. Y.; Liu, L.; Sugiyama, M.; Fu, Y.; Wong, C.-H.
J. Am. Chem. Soc. 2009, 131, 8352. (e) Churches, Q. I.; Stewart, H. E.;
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
§ Graduate School of Chinese Academy of Sciences.
‡ Chengdu Institute of Biology, Chinese Academy of Sciences.
€
Cohen, S. B.; Shroder, A.; Turner, P.; Hutton, C. A. Pure Appl. Chem. 2008,
ꢀ
(1) (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH:
80, 687. (f) Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron 2006,
62, 236. (g) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem.,
€
Weinheim, Germany, 2005. (b) Domling, A. Chem. Rev. 2006, 106, 17. (c)
ꢀ
€
Guillena, G.; Ramon, D. J.;Yus, M. Tetrahedron: Asymmetry 2007, 18, 693.
Int. Ed. 2006, 45, 3635. (h) Koolmeister, T.; Sodergren, M.; Scobie, M.
Tetrahedron Lett. 2002, 43, 5969. (i) Prakash, G. K. S.; Mandal, M.;
Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2002, 67, 3718. (j)
Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A.
Org. Lett. 2000, 2, 3173. (k) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.;
Luke, R. W. A. Chem. Commun. 1996, 1953.
(5) (a) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc.
2007, 129, 6686. (b) Inokuma, T.; Suzuki, Y.; Sakaeda, T.; Takemoto, Y.
Chem.;Asian J. 2011, 6, 2902.
(2) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,
16463. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120,
11798. (e) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539. (f)
Petasis, N. A. Aust. J. Chem. 2007, 60, 795.
(3) For a leading review on Petasis-borono Mannich reaction, see:
Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Chem.
Rev. 2010, 110, 6169.
(6) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
r
10.1021/ol203109a
Published on Web 01/31/2012
2012 American Chemical Society

enantioselective versions are limited to substrates including
quinolines,5a N-aryl-R-imino amides,5b and ethyl glyoxylates.6
Obviously, there is a lack of catalytic enantioselective Petasis
reactions that tolerate variations of both aromatic aldehydes and
readily available arylboronic acids. Indeed, the Petasis reaction
with salicylaldehydes as substrates (Scheme 1, eq 4) should be
an attractive approach for the construction of alkylamino-
phenols,2e which have gathered considerable interest due to
their accessibility to various reagents in organic synthesis and
potential applications in drug discovery and material science.
Therefore, the development of a catalytic enantioselective
Petasis reaction for the three-component reaction among
salicylaldehydes, amines, and organoboronic acids remains
a highly desirable yet elusive goal.
ongoing program on asymmetric organocatalysis,11 we
have recently found that various alkylaminophenols can
be obtained in high yield and good to high enantioselec-
tivity with a newly designed thiourea-binol catalyst 1h
which bears multiple H-bond donors. To the best of our
knowledge, this represents the first catalytic enantioselec-
tive Petasis reaction among salicylaldehydes, amines, and
organoboronic acids. Herein we wish to report our pre-
liminary results on this subject.
Scheme 1. Existing Catalytic Enantioselective Versions of Pet-
asis Reaction
Figure 1. Chiral catalysts evaluated in this study.
Our initial studies started with the reaction of salicylal-
dehyde (2a), morpholine (3a), and (E)-styrylboronic acid
(4a) in ethyl ether at 5 °C for the screening of a series of
chiral organocatalysts 1aÀi (Figure 1).12 As shown in
Table 1, in the presence of 20 mol % chiral 1,2-diamine-
derived thiourea catalysts 1aÀc, the reaction delivered the
desired product 5aaa in only moderate yield and poor
enantioselectivity (entries 1À3). Further investigations
into catalysts 1dÀe which bear thiourea moieties and
hydroxyl groups revealed that 5aaa also could be obtained
with moderate yield and low ee (entries 4À5). Catalyst 1f
rendered the product in 64% yield and 42% ee (entry 6).
Meanwhile, with a multiple H-bond donor thiourea-binol
catalyst 1g, a 68% yield and 8% ee were observed (entry 7).
Because an appropriate match between chiral diamine moi-
ety and the axial chiral BINOL moiety in 1g was likely crucial
for the enantiocontrol, catalyst 1h was prepared and exam-
ined. To our delight, product 5aaa could be obtained in 73%
yield with a significantly improved enantioselectivity of 69%
ee (entry 8). Another catalyst 1i which bears more H-bond
donors was not superior to 1h in terms of enantioselectivity
(entry 9). We then focused on the optimization of a 1h-
Significant progress has been made on the reactions
involving organoboronic reagents with chiral biphenol-
derived diols as catalysts4a,6,7 and on the development of
chiral boronate esters based on the chiral BINOL back-
bone for asymmetric synthesis8 and determination of the
enantiomeric excess of chiral compounds.9 Concurrently,
asymmetric catalysis by chiral H-bond donors represents
an attractive option in organic synthesis.10 As part of our
(7) For selected examples, see: (a) Barnett, D. S.; Schaus, S. E. Org.
Lett. 2011, 13, 4020. (b) Barnett, D. S.; Moquist, P. N.; Schaus, S. E.
Angew. Chem., Int. Ed. 2009, 48, 8679. (c) Bishop, J. A.; Lou, S.; Schaus,
S. E. Angew. Chem., Int. Ed. 2009, 48, 4337. (d) Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (e) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2007, 129, 4908. (f) Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660. (g) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2005, 127, 3244.
(8) For selected examples, see: (a) Lundy, B. J.; Jansone-Popova, S.;
May, J. A. Org. Lett. 2011, 13, 4958. (b) Paton, R. S.; Goodman, J. M.;
Pellegrinet, S. C. J. Org. Chem. 2008, 73, 5078. (c) Pellegrinet, S. C.;
Goodman, J. M. J. Am. Chem. Soc. 2006, 128, 3116. (d) Thormeier, S.;
Carboni, B.; Kaufmann, D. E. J. Organomet. Chem. 2002, 657, 136.
(9) For selected examples, see: (a) Mirri, G.; Bull, S. D.; Horton,
P. N.; James, T. D.; Male, L.; Tucker, J. H. R. J. Am. Chem. Soc. 2010,
(11) Forselected reports from our research group, see: (a) Pei, Q.-L.; Sun,
H.-W.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2011,
76, 7849. (b) Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2011, 13, 5064. (c) Liu, X.-L.; Wu, Z.-J.; Du, X.-L.;
Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2011, 76, 4008. (d) Chen, W.-B.;
Wu, Z.-J.;Hu, J.;Cun, L.-F.;Zhang, X.-M.;Yuan, W.-C.Org. Lett. 2011, 13,
2472. (e) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan,
W.-C. Adv. Synth. Catal. 2011, 353, 1720. (f) Liu, X.-L.; Liao, Y.-H.; Wu,
Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2010, 75, 4872.
(g) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Org. Lett. 2010, 12, 3132. (h) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun,
L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896. (i) Liao, Y.-H.;
Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Adv. Synth. Catal. 2010, 352, 827.
€
132, 8903. (b) Galbraith, E.; Kelly, A. M.; Fossey, J. S.; Kociok-Kohn,
G.; Davidson, M. G.; Bull, S. D.; James, T. D. New J. Chem. 2009, 33,
181. (c) Kelly, A. M.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry
ꢀ
2008, 19, 489. (d) Perez-Fuertes, Y.; Kelly, A. M.; Fossey, J. S.; Powell,
ꢀ
M. E.; Bull, S. D.; James, T. D. Nat. Protoc. 2008, 3, 210. (e) Perez-Fuertes,
Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.; Bull, S. D.; James, T. D. Org.
ꢀ
Lett. 2006, 8, 609.(f)Kelly, A. M.;Perez-Fuertes, Y.; Arimori, S.; Bull, S. D.;
James, T. D. Org. Lett. 2006, 8, 1971.
(10) For representative reviews on asymmetric catalysis by chiral H-bond
donors, see: (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.
(12) For details about the preparation of some selected catalysts, see
Supporting Information.
Org. Lett., Vol. 14, No. 4, 2012
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4h revealed that thiophen-3-ylboronic acid was also tolerated
(entry 14). However, it should be noted that the current
reaction system is ineffective for benzaldehyde derivatives
lacking an o-hydroxy substituent, primary amines, acyclic
secondary amines, and alkyl boronic acids reagents.13
Table 1. Optimization Studiesa
Table 2. Substrate Scopea
a Unless otherwise noted, the reactions were run with 2a (0.1 mmol),
3a (0.1 mmol), and 4a (0.1 mmol) in specified solvent (2.0 mL) with 20
mol % 1 at 5 °C for 24 h. b Isolated yield. c Determined by chiral HPLC.
d Run for 64 h. e Run for 96 h. MTBE = methyl tert-butyl ether.
catalyzed reaction to improve the Petasis reaction efficiency.
A screen of solvents revealed that MTBE was the best solvent
(entry 12 vs entries 8, 10, 11, and 13). Afterward, a survey of
reaction temperatures indicated that performing the reaction
at 5 °C afforded the best results (entry 12 vs entries 14À16).
With the optimal reaction conditions in hand (Table 1,
entry 12), the substrate scope of the three-component
Petasis reaction was surveyed. As shown in Table 2, the
reaction can be extended to a wide variety of salicylalde-
hydes 2aÀd, amines 3aÀd, and organoboronic acids 4aÀh
for the generation of a broad range of alkylaminophenols in up
to 92% yield and up to 95% ee. For the aldehyde component,
not only the salicyaldehyde but also electron-donating (2b) or-
withdrawing (2c) substituent incorporation to the aromatic
ring of salicyaldehyde showed good activities and enantios-
electivities for giving the corresponding products (entries
1À22). The ee value of 5aaa could be readily improved from
73% to 99% after recrystallization from a mixture of petro-
leum ether and ethyl acetate (entry 1). A sterically demanding
aldehyde 2d was also accommodated but with certain impact
on the yield and enantiocontrol (entry 23). We also found
that cyclic secondary amine, including morpholine (3a),
piperidine (3b), pyrrolidine (3c), and even 1,2,3,4-tetrahy-
droisoquinoline (3d), was the most competent partner for
this process. As to the organoboronic acid component,
besides vinyl boronic acid (4a), a variety of arylboronic acids
bearing either an electron-donating (4bÀd) or Àwithdraw-
ing group (4e) are also good substrates for the reaction.
2-Naphthyl-based boronic acid 4g also underwent the Pet-
asis reaction with different amines affording the expected
products with good results (entries 12À13). Importantly,
further extension of this protocol to heteroaryl boronic acid
a The reactions were run with 2 (0.2 mmol), 3 (0.2 mmol), and 4
(0.2 mmol) in MTBE (4.0 mL) with 20 mol % 1h at 5 °C. b Isolated yield.
c Determined by chiral HPLC. d The result in parentheses was obtained with
recrystallization. e Run at 60 °C. f Run at rt. g The absolute configuration of
5dcf was determined to be Rconfiguration by comparing the optical rotation
with the literature known compound.14 The absolute configurations of
remaining products were tentatively assigned by analogy.
We also performed a preparative scale reaction to demon-
strate the practical features of this process. The reaction of
2a, 3c, and 4c was carried out on a gram scale with 20 mol %
catalyst 1h in MTBE. As shown in Scheme 2, the reaction
proceeded well to afford the corresponding product 5acc in
an improved isolated yield up to 87% without any loss of
enantioselectivity (95% ee).
Although a detailed mechanism has yet to be elucidated,
we attempted to conduct preliminary studies on the origin
(13) No desired product was observed when benzaldehyde, phenyl-
methanamine, aniline, dicyclohexylamine, dipentylamine, and cyclopropyl-
boronic acid were used as one component, respectively. However, when
dibenzylamine was used, the expected product could be obtained in only
32% yield, but it was racemate. For details, see Supporting Information.
(14) Periasamy, M.; Reddy, M. N.; Anwar, S. Tetrahedron: Asym-
metry 2004, 15, 1809.
978
Org. Lett., Vol. 14, No. 4, 2012

Scheme 2. Reaction on a Gram Scale
Scheme 3. Comparative Experiments with 1h and 1j as Catalyst
of the enantioselective induction of this process. As shown
in Scheme 3, the use of 1j as the catalyst for the reaction
afforded 5acc in 60% yield but with only 5% ee. In sharp
contrast, with 1h as the catalyst under the same reaction
conditions, a 70% yield and up to 95% ee were observed.
Accordingly, we speculate that the diol functional group of
BINOL in 1h plays a crucial role in asymmetric induction.
Additionally, to obtain further insight into the possible
reaction pathway, we analyzed the 1:5 mixture of 1h and 4b
in MTBE by ESI-MS, observing the mass of the 1:1
complex of 1h and 4b.15 This result indicates that a cyclic
binaphthyl-derived boronate ester fragment was likely
formed by the exchange of the diol group of BINOL in
1h with the hydroxyl groups of boronic acid.15 Never-
theless, we also carried out a control experiment with a
two-component catalyst composed of (R)-BINOL and
(R,R)-bithiourea, furnishing the desired product in 62% yield
but the ee lowered from 95% (Table 2, entry 10) to 31%.16
Finally, we tentatively propose a possible reaction path-
way forthe1h-catalyzed enantioselective Petasis reaction. As
shown in Scheme 4, the nucleophilic addition of the second-
ary amines to salicylaldehydes produces the carbinolamine
intermediate A. Then, the dehydration of the carbinolamine
readily generates a key iminium intermediate B with the
assistance of the o-phenolic hydroxyl group.3,17 Afterward, a
possible reaction intermediate C is proposed, in which the
thiourea is associated to the phenol anion of B.17,18 Simulta-
neously, a cyclic binaphthyl-derived boronate ester fragment
Scheme 4. Possible Reaction Pathway
is formed by the exchange of the diol group of the BINOL
moiety in 1h with the hydroxyl groups of boronic acid.9,15
Subsequently, the R moiety of boronic acids favorably
attacks the iminium ion from the re-face affording the
desired product with R-configuration, while 1h is released
by hydrolysis. Further studies are currently underway to
precisely understand the mechanism of this reaction.
In summary, we have developed an enantioselective three-
component Petasis reaction among salicylaldehydes, second-
ary amines, and organoboronic acids catalyzed by a newly
designed thiourea-binol catalyst. A broad range of alkylami-
nophenols bearing various functional groups can be obtained
in good yield (up to 92%) and good to high enantioselectivity
(up to 95% ee). The potential utility of the protocol has also
been demonstrated by gram-scale reaction. Preliminary
studies on the reaction mechanism were conducted, and a
possible reaction pathway for this catalytic enantioselective
Petasis reaction was tentatively proposed. Further mechan-
istic investigations and expanding the substrate scope are
currently underway in our laboratory.
(15) The ESI-MS spectrum is shown in the Supporting Information.
(16) A control experiment with a two-component catalyst composed
of bithiourea 1a and (R)-BINOL.
(17) For selected examples related to intermediates A and B, see: (a)
ꢀ
Candeias, N. R.; Cal, P. M. S. D.; Andre, V.; Duarte, M. T.; Veiros,
Acknowledgment. We are grateful for financial support
from the NSFC (No. 20802074) and 973 Program (2010C-
B833300). Special thanks are expressed to Prof. Liu-Zhu Gong
(University of Science and Technology of China) and Prof.
Ying-Chun Chen (Sichuan University) for their helpful sugges-
tions to this work.
L. F.; Gois, P. M. P. Tetrahedron 2010, 66, 2736. (b) Tao, J. C.; Li, S. H.
Chin. J. Chem. 2010, 28, 41. (c) Candeias, N. R.; Veiros, L. F.; Afonso,
C. A. M.; Gois, P. M. P. Eur. J. Org. Chem. 2009, 1859.
(18) For selected examples related to H-bond catalysis by anion binding,
see: (a) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2010, 132,
9558. (b) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc.
2011, 133, 14578. (c) Birrell, J. A.; Desrosiers, J.-N.; Jacobsen, E. N. J. Am.
Chem. Soc. 2011, 133, 13872. (d) De, C. K.; Mittal, N.; Seidel, D. J. Am.
Chem. Soc. 2011, 133, 16802. (e) De, C. K.; Seidel, D. J. Am. Chem. Soc.
2011, 133, 14538. (f) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2010, 132, 9286. (g) Klauber, E. G.; De, C. K.; Shah, T. K.;
Seidel, D. J. Am. Chem. Soc. 2010, 132, 13624. (h) De, C. K.; Klauber, E. G.;
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Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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