Metal-free chiral phosphoric acid or chiral metal phosphate as active catalyst in the activation of N -acyl aldimines

Article abstract of DOI:10.1055/s-0030-1260545

Whether metal-free chiral phosphoric acid or chiral metal phosphate functions as an active catalyst was confirmed in three reactions. In the aza-Friedel-Crafts and aza-ene-type reactions, a metal-free chiral phosphoric acid, namely, a chiral Bronsted acid

Full text of DOI:10.1055/s-0030-1260545

CLUSTER
1255
Metal-Free Chiral Phosphoric Acid or Chiral Metal Phosphate as Active
Catalyst in the Activation of N-Acyl Aldimines
Metal-Free
Chiral
P
hos
a
phoric
A
ci
s
d
or Chira
a
l
M
eta
l
Pho
h
sphate iro Terada,* Kyohei Kanomata
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)7956602; E-mail: mterada@m.tohoku.ac.jp
Received 21 February 2011
cium salt of chiral phosphoramide 2a (G = 4-MeOC6H4),6
and treatment of the calcium salt with an acid resulted in
the formation of metal-free, completely protonated, phos-
phoramide 2a that functioned as a catalytically active spe-
Abstract: Whether metal-free chiral phosphoric acid or chiral met-
al phosphate functions as an active catalyst was confirmed in three
reactions. In the aza-Friedel–Crafts and aza-ene-type reactions, a
metal-free chiral phosphoric acid, namely, a chiral Brønsted acid,
was verified to be the active catalyst. In contrast, the substitution cies. Meanwhile, in early 2007, we reported the
reaction of a-diazoacetate with aldimine was accelerated by a salt-
containing chiral phosphoric acid and hence chiral metal phosphate
presumably functioned as an active catalyst.
enantioselective Friedel–Crafts reaction of enecarbamates
3 with indoles 4 catalyzed by 1a (Scheme 1).7 During the
course of this study, we also observed that the catalytic ac-
tivity could be significantly improved by treatment of 1a
with an acid.8 Until the report by Ishihara and co-workers
in 2010,9 it had been considered that metal contamination
affected only the catalytic activity and not the enantio-
selectivity.10 This is because it seems unlikely that alkali
or alkaline-earth metal phosphates would function as an
active catalyst for enantioselective transformations, al-
though the catalytic activities of these metal salts have
been little exploited11,12 with the exception of the activa-
tion of trimethylsilyl cyanide.13 However, in 2010, Ishiha-
ra and co-workers reported that not only metal-free chiral
phosphoric acid but also calcium phosphate functioned as
an efficient enantioselective catalyst for the direct Man-
nich-type reaction of N-Boc aldimines with a broad range
of 1,3-dicarbonyl compounds.9 They also pointed out that
binaphthol-derived chiral phosphoric acids 1 readily cap-
ture adventitious metal impurities, alkali and alkaline-
earth metal salts, during purification using silica gel to
generate a salt-containing chiral phosphoric acid,6b,10,14
and hence the acid treatment of silica gel purified chiral
phosphoric acids 1 has a substantial influence on the cat-
alytic performance. In fact, they clearly demonstrated dif-
ferences in the catalytic performance between calcium
phosphate and metal-free phosphoric acid, where a judi-
cious choice of substituent G introduced at the 3,3¢-posi-
tions of the binaphthyl backbone was required to achieve
high enantioselectivities in the direct Mannich-type reac-
tion. More importantly, these catalysts provided products
with opposite absolute configuration even when catalysts
having the same axial chirality were used. We therefore
confirmed whether metal-free chiral phosphoric acid or
chiral metal phosphate is the active catalyst in the reac-
tions reported before 2006 by our group.15–17 Herein we
report the reaction outcomes using acid-washed, thus met-
al-free, chiral phosphoric acids 1 in three transformations
of N-acyl aldimines, namely, the Friedel–Crafts reac-
tion,15 the substitution reaction of a-diazoacetates,16 and
the aza-ene-type reaction,17 and compared the outcomes
with the results obtained using silica gel purified 1.
Key words: asymmetric catalysis, enantioselectivity, Friedel–
Crafts reaction, organocatalysis, substitution
Chiral Brønsted acids have emerged as efficient catalysts
for enantioselective transformations, and reactions using
these chiral acid catalysts have become a rapidly growing
area in asymmetric synthesis.1 Among the acid catalysts,
binaphthol-derived chiral phosphoric acids 1 indepen-
dently reported by Akiyama and our group in 2004,2 as
well as amide analogues 2 developed by Yamamoto and
Nakashima,3 are some of the most efficient chiral Brøn-
sted acid catalysts identified to date (Figure 1) and have
been utilized as versatile enantioselective catalysts for nu-
merous organic transformations.4
G
G
O
O
O
O
P
P
OH
NHTf
O
O
G
G
(R)-1
(R)-2
Figure 1 Binaphthol-derived chiral phosphoric acids 1 and amide
analogues 2 as chiral Brønsted acid catalysts
In recent years, several researchers have diverted their at-
tention to chiral phosphoric acids contaminated with alka-
li or alkaline-earth metal salts. Ding and co-workers
demonstrated that the treatment of chiral phosphoric acid
with an acid dramatically improved the catalytic activity
in the enantioselective Baeyer–Villiger oxidation,5 al-
though they did not clearly mention the reason for the im-
provement of the catalytic activity. Shortly thereafter,
Rueping and co-workers reported the formation of the cal-
SYNLETT 2011, No. 9, pp 1255–1258
x
x.
x
x.
2
0
1
1
Advanced online publication: 29.04.2011
DOI: 10.1055/s-0030-1260545; Art ID: Y03811ST
© Georg Thieme Verlag Stuttgart · New York

1256
M. Terada, K. Kanomata
CLUSTER
i-Pr
i-Pr
In 2005, we reported the substitution reaction of a-diazo-
acetates 9 with N-benzoyl aldimines 10 catalyzed by 1c
(G = 9-anthryl).16 In the present study, we investigated the
catalytic performance in the substitution reaction using
three types of catalyst 1c (Scheme 3). In the original pa-
per, a-substituted product 11 was afforded as the sole
structural isomer in the presence of silica gel purified 1c.16
In sharp contrast, the catalytic reaction using acid-washed
1c (method A and B) yielded a,b-unsaturated ester 12 as
the sole product, instead of 11. These results imply that
the carbon–carbon bond-forming reaction of a-diazoace-
tates 9 with aldimines 10 was accelerated by either salt-
containing or metal-free chiral phosphoric acid to give in-
termediate A.20,21 The subsequent reaction course was di-
vided into two pathways depending upon the catalyst
employed. Under the influence of silica gel purified 1c,
the salt-containing chiral phosphoric acid, the a-proton of
intermediate A is deprotonated exclusively to give substi-
tution product 11 through path a (indicated by dashed ar-
rows). Although it is not known which metal species of
the salt-containing chiral phosphoric acid functioned as
the active catalyst for the substitution reaction,22 metal-
free acid is not the efficient catalyst for the substitution re-
action and instead, intermediate A undergoes 1,2-migra-
tion of the phenyl group with concomitant elimination of
a nitrogen molecule via path b (indicated by solid arrows)
to yield 12.20,21a
G =
i-Pr
X
Boc
H
HN
(R)-1a (5 mol%)
+
R
MeCN
N
3
H
4
Boc
NH
X
R
N
H
5
acid-washed 1a (ref. 7): ~98%, ~96% ee
silica gel purified 1a:
low reproducibility of yields
but comparable enantioselectivities
Scheme 1 Friedel–Crafts reaction of enecarbamates 3 with indoles
4 catalyzed by acid-washed metal-free chiral phosphoric acid 1a
At the outset, we washed silica gel purified 1 with aque-
ous HCl solution (2 M) to prepare metal-free phosphoric
acid, namely, acid-washed 1 (method A).18 Then, in an ef-
fort to eliminate acid contaminants, acid-washed 1 (meth-
od A) was further subjected to short-path column
chromatography using metal-free extra pure silica gel19 to
afford acid-washed 1 (method B). We initially investigat-
ed the catalytic performance of the three types of phos-
phoric acid 1b (G = hexamethylterphenyl), namely, silica
gel purified15 and acid-washed (method A and B) phos-
phoric acids, in the aza-Friedel–Crafts reaction of N-Boc
aldimines 6 with 2-methoxyfurane (7) (Scheme 2). All
three catalysts 1b exhibited similar catalytic performance
to afford Friedel–Crafts products 8 with comparable enan-
tioselectivities and the same absolute configuration albeit
with a slight decrease in the chemical yield when the two
metal-free acids, acid-washed 1b (method A and B), were
used. These results strongly suggest that metal-free chiral
phosphoric acid is an active catalyst in the aza-Friedel–
Crafts reaction.
NMe2
G =
H
CO2t-Bu
(R)-1c (2 mol%)
+
N
O
toluene, r.t., 24 h
N2
9
Ph
H
10
O
O
p-Me2NC6H4
NH
p-Me2NC6H4
NH
CO2t-Bu
CO2t-Bu
Ph
H
N2
Ph
11
12
silica gel purified 1c (ref. 16): 11 in 81%, 97% ee (S)
acid-washed 1c (method A):
acid-washed 1c (method B):
not detected 11 (12 in 63%)
G =
not detected
11 (12 in 62%)
Boc
N
O
(R)-1b (2 mol%)
O
+
OMe
(H)
N
(CH2Cl)2, –35 °C, 24 h
Ph
H
p-Me2NC6H4
6
7
N
path b
Ph
N
path a
CO2t-Bu
Boc
H
NH
A
O
Ph
OMe
Scheme 3 Reaction of a-diazoacetates 9 with N-benzoyl aldimines
10
8
silica gel purified 1b (ref. 15): 87%, 97% ee (R)
acid-washed 1b (method A): 76%, 93% ee (R)
acid-washed 1b (method B): 78%, 95% ee (R)
Finally, we examined the aza-ene-type reaction of N-ben-
zoyl aldimines 13 with enecarbamates 14 using three
types of chiral phosphoric acid 1c (Scheme 4).17 In the
previous report, silica gel purified 1c displayed marked
Scheme 2 Aza-Friedel–Crafts reaction of N-Boc aldimines 6 with
2-methoxyfurane (7)
Synlett 2011, No. 9, 1255–1258 © Thieme Stuttgart · New York

CLUSTER
Metal-Free Chiral Phosphoric Acid or Chiral Metal Phosphate
1257
catalytic efficiency, and the catalyst loading could be re- mining the purity of a compound.14 On the other hand, the
duced to as low as 0.05 mol%. However, in the evaluation accidental use of salt-containing chiral phosphoric acid
of the catalytic performance, we employed 2 mol% each has opened new avenues in the field of enantioselective
of 1c to exclude experimental errors. The reaction cata- catalysis. Indeed, after the report by Ishihara and co-work-
lyzed by acid-washed 1c (method A and B) proceeded ers,9 a couple of excellent enantioselective catalyses have
smoothly. After the hydrolysis of imine products 15, cor- been accomplished by means of chiral calcium phos-
responding ketones 16 were obtained in nearly quantita- phates.12 The derivatization of chiral phosphoric acids
tive yields and hence the metal-free acids are catalytically with alkali, alkaline-earth, and other metal salts has broad-
more active than the salt-containing acid, silica gel puri- ened the scope for the development of enantioselective ca-
fied 1c. In addition, the absolute stereochemistry of ke- talysis by chiral phosphate salts.11 Further studies along
tones 16 was the same R configuration for all cases albeit this line are in due course in our laboratory.
a slight decrease in enantioselectivity. These results clear-
ly reveal that the aza-ene-type reaction is efficiently cata-
lyzed by metal-free chiral phosphoric acid, not by chiral
Acknowledgment
This work was supported by JSPS through a Grant-in-Aid for Sci-
entific Research (Grant No. 20245021).
metal phosphate.
Ph
CO2Me
Ph
References and Notes
(R)-1c (2 mol%)
HN
N
O
+
toluene, r.t., 1 h
(1) For reviews, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713. (b) Akiyama, T. Chem. Rev. 2007,
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Ph
H
13
14
Bz
Bz
NH NCO2Me
HBr
MeOH, r.t., 30 min
NH
O
Ph
Ph
Ph
Ph
15
16
silica gel purified 1c (ref. 17):
acid-washed 1c (method A):
acid-washed 1c (method B):
85%, 95% ee (R)
>99%,
98%,
93% ee (R)
93% ee (R)
Scheme 4 Aza-ene-type reaction of N-benzoyl aldimines 13 with
enecarbamates 14
(3) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006,
128, 9626. For a review, see: (b) Cheon, C. H.; Yamamoto,
H. Chem. Commun. 2011, 47, 3043.
In summary, we have documented whether metal-free
chiral phosphoric acid or chiral metal phosphate func-
tioned as an active catalyst in three reactions. In the aza-
Friedel–Crafts and aza-ene-type reactions, a metal-free
acid, namely, chiral Brønsted acid, was verified to be the
active catalyst by comparing its reaction outcome with
those of silica gel purified and acid-washed chiral phos-
phoric acids. In contrast, we ascertained that the substitu-
tion reaction of a-diazoacetate with aldimine is efficiently
accelerated by the silica gel purified acid catalyst, where
chiral metal phosphate presumably participates in the cat-
alytic cycle.
(4) For reviews, see: (a) Connon, S. J. Angew. Chem. Int. Ed.
2006, 45, 3909. (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999. (c) Adair, G.; Mukherjee, S.;
List, B. Aldrichimica Acta 2008, 41, 31. (d) Terada, M.
Chem. Commun. 2008, 4097. (e) Terada, M. Bull. Chem.
Soc. Jpn. 2010, 83, 101. (f) Terada, M. Synthesis 2010,
1929. (g) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva,
S. B. Org. Biomol. Chem. 2010, 8, 5262.
(5) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew.
Chem. Int. Ed. 2008, 47, 2840.
(6) (a) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R.
M. Angew. Chem. Int. Ed. 2008, 47, 6798. (b) Rueping, M.;
Nachtsheim, B. J.; Koenigs, R. M.; Ieawsuwan, W. Chem.
Eur. J. 2010, 16, 13116.
As summarized above, either Brønsted acid or metal
phosphate is catalytically active, although their activities
are dependent on the type of reaction. In past experiments,
our unintentional use of silica gel purified ‘salt-contain-
ing’ chiral phosphoric acids led to substantial confusion in
the development of chiral Brønsted acid catalysis. We
identified chiral phosphoric acids by HRMS, NMR, and
IR spectroscopy, despite the fact that these analytical
methods are not effective for the detection of the forma-
tion of metal salts. Our lack of detailed attention to struc-
tural identification is responsible for the erroneous full
characterization of silica gel purified chiral phosphoric
acids. Elemental analysis is clearly more important than
HRMS for identifying elemental composition and deter-
(7) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292.
(8) Sorimachi, K.; Terada, M. unpublished results.
(9) Ishihara and co-workers reported that the outcome of the
Mannich reaction of N-Boc aldimine 6 with acetylacetone
catalyzed by chiral calcium phosphate [G = 4-(b-naphthyl)
phenyl] was comparable to our reported result (see ref. 2b)
obtained using silica gel purified chiral phosphoric acid
(G = same as above), see: (a) Hatano, M.; Moriyama, K.;
Maki, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010, 49,
3823. Also see: (b) Hatano, M.; Ishihara, K. Synthesis 2010,
3785.
(10) List and co-workers compared the catalytic activities of
metal-free and silica gel purified, i.e., salt-containing
phosphoric acids 1a in an asymmetric transfer hydro-
genation of imine. They reported that both acids yielded the
corresponding products with the same enantioselectivity.
Synlett 2011, No. 9, 1255–1258 © Thieme Stuttgart · New York

1258
M. Terada, K. Kanomata
CLUSTER
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(a) Klussmann, M.; Ratjen, L.; Hoffmann, S.; Wakchaure,
V.; Goddard, R.; List, B. Synlett 2010, 2189. Also see:
(b) Lu, G.; Birman, V. B. Org. Lett. 2011, 13, 356.
(14) List and co-workers reported that silica gel purified chiral
phosphoric acid 1a contained substantial amounts of alkali
and alkaline-earth metals along with several metal
impurities as ascertained by ICP-OES elemental analysis.
See ref. 10a.
(11) Selected examples of binaphthol-derived monophosphoric
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(e) LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.;
Toste, F. D. Angew. Chem. Int. Ed. 2010, 49, 598. For
copper catalysts, see: (f) Zhao, B.; Du, H.; Shi, Y. J. Org.
Chem. 2009, 74, 8392. For silver catalysts, see: (g) Zhang,
Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.;
Gu, P.; Chen, Z.-M. Angew. Chem. Int. Ed. 2009, 48, 8572 .
For iron catalysts, see: (h) Yang, L.; Zhu, Q.; Guo, S.; Qian,
B.; Xia, C.; Huang, H. Chem. Eur. J. 2010, 16, 1638. For
rare-earth metal catalysts, see: (i) Inanaga, J.; Sugimoto, Y.;
Hanamoto, T. New J. Chem. 1995, 19, 707. (j) Furuno, H.;
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(12) After the report by Ishihara and co-workers, the
enantioselective catalysis by chiral calcium phosphate was
developed by three research groups, see: (a) Drouet, F.;
Lalli, C.; Liu, H.; Masson, G.; Zhu, J. Org. Lett. 2011, 13,
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(15) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
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(16) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
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(17) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem. Int.
Ed. 2006, 45, 2254.
(18) For the Preparation of Acid-Washed 1b (Method A)
Silica gel purified 1b was dissolved in Et2O. The resultant
solution was washed with HCl aq solution (2 M) in a
separatory funnel. The resultant ether layer was dried over
Na2SO4 and evaporated to remove organic solvents. The
resultant residue was dried under reduced pressure for more
than 12 h to eliminate organic solvents completely.
For the Preparation of Acid-Washed 1c (Method A)
Silica gel purified 1c was dissolved in MeOH. Then HCl aq
solution (2 M) was added to the resultant MeOH solution to
give a white suspension. The resultant suspension was
extracted with CH2Cl2 (twice or more), and the combined
organic layer was dried over Na2SO4. This was followed by
the procedure as shown in the preparation of acid-washed 1b
(method A).
(19) Extra pure silica gel (Silica gel 60 extra pure for column
chromatography: Catalogue No. 1.07754) was purchased
from Merck KgaA. Short-path column chromatography was
performed using CH2Cl2–MeOH (10:1) mixtures as eluent.
(20) For the enantioselective substitution reaction of a-diazo-
acetates with aldimines catalyzed by chiral Brønsted acids,
see: (a) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2007, 129, 10054. (b) Hashimoto, T.; Maruoka, K. Synthesis
2008, 3703.
(21) For the enantioselective aziridine formation (aza-Darzens)
reaction of a-diazoacetates with aldimines catalyzed by
chiral Brønsted acids, see: (a) Hashimoto, T.; Uchiyama,
N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380.
(b) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11,
2445. (c) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org.
Lett. 2009, 11, 3036.
(22) A silica gel purified chiral phosphoric acid contains
considerable amounts of alkali and alkaline-earth metals
with other metal impurities. Therefore it should be
considered that a problem of reproducibility in yield and
selectivity would happen, because the composition of metals
is dependent on the conditions of silica gel column
chromatography conducted.
(13) In the reaction of trimethylsilyl cyanide, the formation of
hypervalent silicate might be responsible for the acceleration
of the reactions, see: (a) Hatano, M.; Ikeno, T.; Matsumura,
Synlett 2011, No. 9, 1255–1258 © Thieme Stuttgart · New York