The Acceleration of the Rearrangement of α-Hydroxy Aldimines by Lewis or Bronsted Acids

Article abstract of DOI:10.1055/s-0037-1610262

An efficient method was developed for the synthesis of α-amino ketones from α-hydroxy imines. The reaction occurs through an α-iminol rearrangement involving the migration of a substituent of the carbinol carbon to the imine carbon. The optimal catalysts were found to be silica gel or montmorillonite K 10, which effected migration of a variety of aryl and alkyl substituents in high yields. The rearrangement can also be carried out on imines generated in situ from aldehydes and amines in essentially the same yields as those from the preformed imines.

Full text of DOI:10.1055/s-0037-1610262

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
X. Zhang et al.
Letter
Synlett
The Acceleration of the Rearrangement of -Hydroxy Aldimines
by Lewis or Brønsted Acids
R2
H
Xin Zhang
R2
N
NH
silica gel
R1
Yijing Dai
R1
R1
R1
OR
William D. Wulff*
Montmorillonite K 10
OH
O
Department of Chemistry, Michigan State University, East Lansing,
MI 48824, USA
wulff@chemistry.msu.edu
18 examples
28–100% yield
R1 = aryl, alkyl
R2 = aryl
Received: 03.08.2018
Accepted after revision: 05.08.2018
Published online: 28.08.2018
We recently reported the first catalytic asymmetric -im-
inol rearrangement promoted by a VANOL (3,3′-diphenyl-
2,2′-binaphthalen-1-ol) complex of zirconium.4
DOI: 10.1055/s-0037-1610262; Art ID: st-2018-b0374-l
All the reported examples of the -iminol rearrange-
ment involve imines derived from ketones and therefore it
was of interest to study the rearrangement of -hydroxy
aldimines in the presence or absence of simple Brønsted
and Lewis acids.5 The test substrate 1 was subjected to
strictly thermal conditions in the presence of air, and it was
found that the product 2 could not be detected after heating
at 80ꢀ°C for 42ꢀh (Tableꢀ1, entry 1). Increasing the tempera-
ture to 150ꢀ°C for two hours gave the rearrangement prod-
uct 2 in 20ꢀ% yield, along with a 30ꢀ% recovery of 1 and a 50ꢀ%
yield of the imine 3, which presumably results from the ae-
rial oxidation of the amine 2. Acetic acid and sulfuric acid
were not effective catalysts, except when the latter was
used in DMF as solvent, which gave a 90ꢀ% yield of 2 in the
presence of air (entry 8). One equivalent of 4-toluenesul-
fonic acid hydrate gave a 56ꢀ% yield of 2 along with a 44ꢀ%
yield of the aldehyde resulting from the hydrolysis of 1 (en-
try 10). Lewis acids including zinc, copper, and scandium
triflates gave moderate yields under certain conditions, but
the none of these reactions could be optimized to provide
useful levels of product. A useful outcome was also not real-
ized with the reaction mediated by sodium ethoxide, which
gave 100ꢀ% conversion to a complex mixture of products. Fi-
nally, it was found that a very efficient and clean rearrange-
ment of 1 could be affected with either silica gel or mont-
morillonite K 10 as catalyst, which gave 95 and 100ꢀ% yields
at 80 and 60ꢀ°C, respectively (entries 22 and 23).
Abstract An efficient method was developed for the synthesis of
-amino ketones from -hydroxy imines. The reaction occurs through
an -iminol rearrangement involving the migration of a substituent of
the carbinol carbon to the imine carbon. The optimal catalysts were
found to be silica gel or montmorillonite K 10, which effected migration
of a variety of aryl and alkyl substituents in high yields. The rearrange-
ment can also be carried out on imines generated in situ from alde-
hydes and amines in essentially the same yields as those from the pre-
formed imines.
Key words iminol rearrangement, silica gel, montmorillonite, cataly-
sis, amino ketone, hydroxy imines
The -iminol rearrangement converts an -hydroxy
imine into an -amino ketone. The history and the develop-
ment of this reaction have been documented in a review
that appeared in 2003;1 subsequently, there have been
many additional examples of this reaction.2,3 The rear-
rangement is reversible and the equilibrium can lie either
with the ketone or the imine; although this very much de-
pends on the structure of the substrate, typically the equi-
librium lies with the ketone. In the presence of a protic acid
the equilibrium is driven toward the -amino ketone be-
cause the amine salt is not an active participant in the equi-
librium. Most examples reported in the literature involved
thermal conditions (about 150ꢀ–ꢀ200ꢀ°C), but the reaction
can be accelerated by simple Brønsted acids,1,2 transition-
metal Lewis acids,2f,j,r or, in some cases, by alkoxide bases.1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
X. Zhang et al.
Letter
Synlett
Table 1 Effects of Brønsted and Lewis acids on the -Iminol Rear-
syntheses of the rearrangement precursors 1 all began from
the commercially available ethyl diethoxyacetate (3) and
the appropriate Grignard reagent.4 The silica gel-mediated
rearrangements were carried out at 80ꢀ°C for one hour in
the presence of air. A variety of aryl groups in the iminol
gave excellent yields when a methyl group was incorporat-
ed in any of the three positions of the arene, including the
ortho-position. Incorporation of larger groups such as phe-
nyl and isobutyl in the para-positions also resulted in excel-
lent yields (89ꢀ–ꢀ99ꢀ%). An excellent yield was also observed
with the electron-rich para-anisyl group (88ꢀ%), but the re-
action of the electron-withdrawing para-trifluoromethyl-
substituted reactant was particularly problematic. Under
the standard conditions, none of the expected -amino ke-
tone 2ꢀl was obtained, and the reaction was very slow, going
only to 20ꢀ% completion in 24 hours. The only product ob-
served was the -ketoimine resulting from air oxidation of
2ꢀl. It was surprising that the electron-rich -amino ketone
2j was not more susceptible to air oxidation to an imine.
When the rearrangement of 1ꢀl was carried out under nitro-
gen, ketone 2ꢀl was isolated, but only in 28ꢀ% yield with
montmorillonite K-10 as catalyst. The reaction of alkyl-sub-
stituted iminols also gave good yields. The biscyclohexyl
iminol 1n gave the -amino ketone 2n in 85ꢀ% yield. The re-
arrangement of the bishexyl iminol 1ꢀm was a little slower
and required a temperature of 90ꢀ°C to go to completion,
giving 2ꢀm in 62ꢀ% yield. The yield was increased to 85ꢀ% by
using montmorillonite K-10 (60ꢀ°C, 10ꢀh).
It was determined that this method could be extended
to the synthesis of -amino ketones with a removable pro-
tecting group on the nitrogen atom. Reaction of aldehyde 4a
with 4-methoxyaniline gave the imine 5 quantitatively;
heating this compound at 80ꢀ°C with silica gel gave the de-
sired -amino ketone 6 in 65ꢀ% yield, along with the oxi-
dized product 7 in 32ꢀ% yield (Scheme 2). The oxidation
product 7 was clearly the result of aerial oxidation, because
it was completely absent when the same reaction was per-
formed under a nitrogen atmosphere, where a 92ꢀ% yield of
6 was obtained. Oxidation with air was much less of a prob-
lem with montmorillonite K 10 as catalyst, because this
gave -amino ketone 6 in 90ꢀ% yield along with only a 5ꢀ%
yield of 7.
rangementa
Ph
Ph
Ph
Ph
Ph
N
N
catalyst
NH
Ph
Ph
Ph
H
Ph
solvent, temp
time
OH
O
O
1
2
3
Entry Catalyst
Catalyst
amount
Solvent
T (°C) Time Yieldb
(h)
(%) of 2
1
ꢀ–ꢀ
ꢀ–ꢀ
toluene
80
42
0
2
ꢀ–ꢀ
ꢀ–ꢀ
mesitylene 150
2
20c
ꢀ–ꢀd
ꢀ<ꢀ1e
0f
3
HOAc
HOAc
HOAc
H2SO4
10 equiv
1 equiv
1 equiv
1 equiv
toluene
toluene
DMF
80
80
80
80
60
80
80
80
80
80
80
80
80
80
80
80
80
80
60
80
60
10
15
1
4
5
6
toluene
toluene
DMF
1
ꢀ–ꢀg
13
90
0f
7
H2SO4/SiO2 1 equiv
1.5
1
8
H2SO4
1 equiv
0.1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
100 wt%
100 wt%
100 wt%
9
H2SO4
DMF
3.5
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
TsOH·H2O
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Sc(OTf)2
Sc(OTf)2
NaOEt
DMF
56h
9i
DMF
2
DMF
1
ꢀ–ꢀj
toluene
PhCF3
DMF
1
25k
30
0l
1
1
toluene
PhCF3
DMF
1
ꢀ–ꢀm
38
71
50
ꢀ–ꢀn
1
1
PhCF3
EtOH
1
1
silica gel
silica gel
K 10q
toluene
toluene
toluene
2
30o
95p
100
1
1.5
a Unless otherwise specified, all reactions were carried out on 0.1ꢀmmol
scale in the presence of air.
b Yield determined from the 1H NMR spectrum of the crude reaction mix-
ture with triphenylmethane as internal standard.
c A 30ꢀ% recovery of 1 and a 50ꢀ% yield of 3 were obtained.
d A 40ꢀ% recovery of 1 and a 60ꢀ% yield of 3 were obtained.
e ꢀ>ꢀ99ꢀ% recovery of 1;ꢀ<ꢀ1ꢀ% formation of 2.
f 100ꢀ% recovery of 1.
An additional advantage of the present protocol for the
-iminol rearrangement over those with more-convention-
al catalysts is its toleration of acid-sensitive groups, as illus-
trated by the rearrangement of iminol 8 bearing a TBS ether
group (Tableꢀ2). With sulfuric acid as catalyst, the rear-
rangement occurred at 80ꢀ°C with concomitant loss of the
TBS group to give the alcohol 10 in 56ꢀ% yield. In contrast,
the rearrangement with montmorillonite K 10ꢀat 70ꢀ°C gave
a 96ꢀ% yield of the -amino ketone 9 with an intact TBS
group.
g This reaction gave an insoluble black resin.
h A 44ꢀ% yield of aldehyde 4 from hydrolysis of 1 was also obtained.
i 91ꢀ% recovery of 1.
j 70ꢀ% recovery of 1.
k 100ꢀ% conversion.
l 30ꢀ% recovery of 1.
m 50ꢀ% recovery of 1
n 100ꢀ% conversion; complex mixture obtained.
o 70ꢀ% conversion.
p With a different batch of silica gel, the yield was 87ꢀ% after 2ꢀh.
q Montmorillonite K 10.
We then turned our attention to investigating the scope
of the silica gel-mediated rearrangement with a variety of
-iminols 1, and the results are presented in Scheme 2.6 The
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
X. Zhang et al.
Letter
Synlett
PMP
H
Ph
H
O
N
O
EtO OEt
N
MeO
NH2
Ph
Ph
R
2 RMgBr
PhNH2
KHSO4
R
OEt
H
Ph
Ph
H
H
R
R
toluene
OH
OH
O
OH
OH
catalyst
toluene
4a
3
4
1
5 100%
Ph
Ph
N
100 wt% silica gel, 80 °C, 3 h
NH
R
R
silica gel
toluene, 80 °C, 1 h
6
7
PMP
R
PMP
H
NH
R
under air
under N2
65% 32%
92% 0%
N
+
OH
Ph
O
Ph
O
1
2
Ph
Ph
Product 2, yield (%)
Product 2, yield (%)
O
100 wt% Montmorillonite K 10, 60 °C, 10 h
6
7
6
7
Ph
Ph
under air
90%
5%
NH
NH
Scheme 2 -Iminol rearrangement of imine 5
Table 2 -Iminol Rearrangement in the Presence of a Silyl Ether
O
O
2a 95%
2h 89%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NH
NH
NH
NH
NH
TBSO
RO
catalyst
N
NH
O
O
O
O
O
Ph
Ph
conditions
2b 92%
2i 99%
Ph
H
Ph
Ph
OMe
OH
NH
O
8
9 R = OTBS
10 R = H
O
O
O
Catalyst
T (°C) Time (h) Yieldb
(%) of 9 of 10
Yieldb (%)
2j 88%
MeO
Catalyst
amount
Solvent
2c 90%
2d 99%
F
NH
NH
H2SO4
silica gel
K 10c
1 equiv
DMF
80
80
70
1
1
2
ꢀ–ꢀ
56
ꢀ–ꢀ
100 wt%
100 wt%
toluene
toluene
70
96
2k 85%
F
ꢀ–ꢀ
CF3
a Unless otherwise specified, all reactions were carried out on a 0.1ꢀmmol
scale in the presence of air.
b Yield determined by 1H NMR spectroscopy of the crude reaction mixture
with triphenylmethane as internal standard.
c Montmorillonite K 10.
2e 90%
2l 0%a (28%)b
F3C
Ph
Ph
NH
NH
It was also found that the protocol for the -iminol rear-
rangement can be greatly simplified by combining the
imine formation and subsequent rearrangement in a single
step (Scheme 3). Heating the aldehyde 4a with 1.1 equiva-
lents of aniline at 80ꢀ°C in air in the presence of silica gel or
montmorillonite K 10 gave the -amino ketone 2a in 80ꢀ%
and 95ꢀ% yield, respectively.
O
O
2f 97%
2m 62%c (85%)d
Ph
NH
Ph
NH
O
O
2g 78%
2n 85%
Scheme 1 Substrate scope for the -iminol rearrangement of iminols
1 with silica gel. Unless otherwise specified, all reactions were carried
out with imine 1 (0.1ꢀmmol) and silica gel (100 wt%) gel in toluene at
80ꢀ°C for 1ꢀh in the presence of air. The reported yield is that of the iso-
lated material purified by silica gel chromatography. a The reaction time
was 24ꢀh and the conversion was 20ꢀ%. The only product observed was
the -keto imine resulting from aerial oxidation of 2ꢀl. b Reaction with
100 wt% montmorillonite K 10ꢀat 70ꢀ°C for 24ꢀh under a N2 atmosphere. c
Reaction temperature: 90ꢀ°C. d Reaction with 100 wt% montmorillonite
K 10ꢀat 60ꢀ°C for 10ꢀh.
Ph
NH2
1.1 equiv
O
NH
Ph
H
Ph
catalyst
toluene, air
OH
O
4a
2a
100 wt% silica gel, 80 °C, 3.5 h
80% of 2a
100 wt% Montmorillonite K 10, 60 °C, 4 h
95% of 2a
Scheme 3 Concomitant imine formation and -iminol rearrangement
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
X. Zhang et al.
Letter
Synlett
We were able to extend this rearrangement to the ket-
imine 11, prepared according to the method reported by
Stevens et al.7 Heating imine 11 with silica gel at 120ꢀ°C led
to ring expansion and the formation of the -amino ketone
12 in 83ꢀ% yield (Scheme 4). This transformation demon-
strates that the -iminol rearrangement can be used to ac-
cess analogues of ketamine 13, which has been used since
1963 as a short-term anesthetic.2a,8
2008, 10, 4009. (g) Fuji, H.; Ogawa, R.; Ohata, K.; Nemoto, T.;
Makajima, M.; Hasebe, K.; Mochizuki, H.; Nagase, H. Bioorg.
Med. Chem. 2009, 17, 5983. (h) Lu, G.; Katoh, A.; Zhang, Z.; Hu,
Z.; Lei, P.; Kimura, M. J. Heterocycl. Chem. 2010, 47, 932. (i) Yang,
T.-F.; Shen, C.-H.; Hsu, C.-T.; Chen, L.-H.; Chuang, C.-H. Tetrahe-
dron 2010, 66, 8734. (j) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem.
Soc. 2011, 133, 10050. (k) Han, S.; Movassaghi, M. J. Am. Chem.
Soc. 2011, 133, 10768. (l) Liu, S.; Hao, X.-J. Tetrahedron Lett.
2011, 52, 5640. (m) Harayan, A. R. N.; Sarpong, R. Org. Biomol.
Chem. 2012, 10, 70. (n) Fustero, S.; Albert, L.; Maten, N.; Chiva,
G.; Miró, J.; González, J.; Aceña, J. L. Chem. Eur. J. 2012, 18, 3753.
(o) Yang, T.-F.; Chen, L.-H.; Kao, L.-T.; Chuang, C.-H.; Chen, Y.-Y.
J. Chin. Chem. Soc. (Weinheim, Ger.) 2012, 59, 378. (p) Hays, P. A.;
Casale, J. F.; Berrier, A. L. Microgram J. 2012, 9, 3. (q) Ahmadi, A.;
Khalili, M.; Hajikhani, R.; Hosseini, H.; Afhin, N.; Nahri-Niknafs,
B. Med. Chem. (Sharjah, United Arab Emirates) 2012, 8, 246.
(r) Liu, S.; Scotti, J. S.; Kozmin, S. A. J. Org. Chem. 2013, 78, 8645.
(s) Zhang, Z.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett.
2013, 15, 4822. (t) Frongia, A.; Secci, F.; Capitta, F.; Piras, P. P.;
Sanna, M. L. Chem. Commun. 2013, 49, 8812.
Ph
O
N
Ph
NH
OH
100 wt% silica gel
mesitylene
120 °C, 48 h
11
12 83%
O
Me
NH
Cl
(S)-ketamine 13
(3) For recent examples of other methods for the synthesis of -
amino ketones, see: (a) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem.
Commun. 2007, 852. (b) Liu, L.; Zheng, Y.; Hu, X.; Lian, C.; Yuan,
W.; Zhang, X. Chem. Res. Chin. Univ. 2014, 30, 235. (c) Farahi, M.;
Tamaddon, F.; Karami, B.; Pasdar, S. Tetrahedron Lett. 2015, 56,
1887. (d) Wen, W.; Zeng, Y.; Peng, L.-Y.; Fu, L.-N.; Guo, Q.-X. Org.
Lett. 2015, 17, 3922. (e) Tamaddon, F.; Tafti, A. D. Synlett 2016,
27, 2217. (f) Lin, L.; Bai, X.; Ye, X.; Zhao, X.; Tan, C.-H.; Jiang, Z.
Angew. Chem. Int. Ed. 2017, 56, 13842.
(4) Zhang, X.; Staples, R. J.; Rheingold, A. L.; Wulff, W. D. J. Am.
Chem. Soc. 2014, 136, 13971.
(5) Our recent report on catalytic asymmetric -iminol rearrange-
ment is the single exception in the case of aldimines (see ref. 4).
(6) 1,2-Diphenyl-2-(phenylamino)ethanone (2a); Typical Proce-
dure
A slurry of imine 1a (0.0287 g, 0.100 mmol) and silica gel
(0.0280 g) in toluene (0.3 mL) was placed in a 20 mL vial under
air, and the vial was sealed with a screw-cap and heated at 80 °C
for 1 h. Alternatively, a slurry of 1a (0.0287 g, 0.100 mmol) and
montmorillonite K (0.0285 g) in toluene (0.3 mL) was placed in
a 20 mL vial under air, and the vial was sealed with a screw-cap
and heated at 60 °C for 1.5 h. After the solution had cooled to r.t.,
it was concentrated on a rotary evaporator and the residue was
purified by flash column chromatography [silica gel, hexane–
CHCl3 (1:2)] to give a yellow solid; yield: 0.0272 g (95%, 0.0948
mmol) (with silica gel) or 0.0287 g (100%) (with montmorillon-
ite K 10); mp = 89–92 °C.1H NMR (500 MHz, CDCl3):  = 5.62 (br
s, 1 H), 6.04 (s, 1 H), 6.70–6.72 (m, 3 H), 7.14 (t, J = 8.0 Hz, 2 H),
7.21 (t, J = 7.5 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 2 H), 7.42–7.46 (m, 4
H), 7.52 (t, J = 7.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3):  = 62.88, 113.72, 118.04, 128.11, 128.15, 128.66,
128.85, 129.04, 129.22, 133.49, 135.05, 137.56, 145.90, 196.97.
(7) Stevens, C. L.; Thuillier, A.; Daniher, F. A. J. Org. Chem. 1965, 30,
2962.
Scheme 4 Synthesis of a ketamine analogue through an -iminol rear-
rangement
In conclusion, we found that the -iminol rearrange-
ment of aldimines and ketimines can be affected with silica
gel or montmorillonite K 10 to give the corresponding -
amino ketones in excellent yields at moderate temperatures
(60ꢀ–ꢀ80ꢀ°C) in the presence of air. The reaction scope is gen-
eral for the migration of a variety of aryl and alkyl groups,
the only exception observed being that of the 4-trifluoro-
methyl group.ꢀThese catalysts also are effective for the rear-
rangement of imines generated in situ from aldehydes and
an amine. The conditions are sufficiently mild to accommo-
date a silyl enol ether without cleavage or to permit exten-
sion to imines of ketones, as illustrated for the synthesis of
an analogue of the anesthetic ketamine.
Funding Information
This work was supported by a grant from the National Institute of
General Medical Sciences (GM094478).
N
oaitn
a
l
nItusite
of
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n
era
l
M
e
dcai
l
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M
0
9
4
4
7
8)
References and Notes
(1) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477.
(2) (a) Brunner, H.; Kagan, H. B.; Kreutzer, G. Tetrahedron: Asymme-
try 2003, 14, 2177. (b) Liu, Y.; McWhorter, W. W. Jr; Hadden, C.
E. Org. Lett. 2003, 5, 333. (c) Liu, Y.; McWhorter, W. W. Jr J. Org.
Chem. 2003, 68, 2618. (d) Liu, Y.; McWhorter, W. W. Jr J. Am.
Chem. Soc. 2003, 125, 4240. (e) Binder, J. T.; Crone, B.; Kirsch, S.
F.; Liébert, C.; Menz, H. Eur. J. Org. Chem. 2007, 1636.
(f) Movassaghi, M.; Schmidt, M. A.; Ashenjurst, J. A. Org. Lett.
(8) Yokoyama, R.; Matsumoto, S.; Momura, S.; Higaki, T.; Yokoyama,
T.; Kiyooka, S.-i. Tetrahedron 2009, 65, 5181.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D