Catalytic Enantioselective Povarov Reactions of Ferrocenecarbaldehyde-Derived Imines – Br?nsted Acid Catalysis at Parts-Per-Million Level Loading

Article abstract of DOI:10.1002/adsc.201701484

Despite the broad interest in ferrocene containing compounds, ferrocenyl substrates have been employed in catalytic asymmetric settings only sporadically. Herein, catalytic asymmetric Povarov reactions with ferrocenecarbaldehyde-derived N-aryl imines are

Full text of DOI:10.1002/adsc.201701484

Title: Catalytic Enantioselective Povarov Reactions of
Ferrocenecarbaldehyde-Derived Imines – Brønsted Acid
Catalysis at Parts-Per-Million Level Loading
Authors: Dragana Stevanovic, Giulio Bertuzzi, Andrea Mazzanti,
Mariafrancesca Fochi, and Luca Bernardi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701484
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalytic Enantioselective Povarov Reactions of
Ferrocenecarbaldehyde-Derived Imines – Brønsted Acid
Catalysis at Parts-Per-Million Level Loading
Dragana Stevanović,a,b Giulio Bertuzzi,a Andrea Mazzanti,a Mariafrancesca Fochi,a*
and Luca Bernardia*
a
Department of Industrial Chemistry “Toso Montanari” & INSTM RU Bologna, Alma Mater Studiorum University of
Bologna, V. Risorgimento 4, 40136 Bologna (Italy)
E-mail: mariafrancesca.fochi@unibo.it; luca.bernardi2@unibo.it
Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac
b
(Serbia)
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
i) the potential interesting features of products 4:
compounds, ferrocenyl substrates have been employed in while the 1,2,3,4-tetrahydroquinoline scaffold is itself
Abstract. Despite the broad interest in ferrocene containing
catalytic asymmetric settings only sporadically. Herein,
catalytic asymmetric Povarov reactions with
a
very common unit in biologically active
compounds,[8] the insertion of a ferrocene unit in a
molecular structure has sometimes resulted in
ferrocenecarbaldehyde-derived N-aryl imines are presented.
This study demonstrates that the stereoelectronic properties
of ferrocenyl imines do not preclude their engagement in
enantioselective phosphoric acid catalysis: cycloadducts
derived from benzyl N-vinylcarbamate were obtained in
good yields and nearly enantiopure form using 0.1 mol% of
a standard Brønsted acid catalyst. Furthermore, it is shown
that specific optimisation with some substrates allowed to
lower the catalyst loading up to 10-20 parts-per-million, an
unprecedented value for phosphoric acid catalysts. Such
low loading protocol could be applied to a preparative scale
reaction, and to imines derived from arylaldehydes.
dramatic
improvements
of
its
biological
properties;[2,3]
ii) the curiosity to explore the behaviour of imines
1 in catalytic asymmetric settings: to our knowledge,
ferrocenecarbaldehyde and its imine derivatives 1
have not been so far investigated in chiral Brønsted
acid catalysed reactions.[9] We were thus wondering
how these substrates, which possess some unusual
stereoelectronic properties, would have responded to
common catalytic systems.
Keywords: Asymmetric Catalysis; Ferrocene;
Organocatalysis; Phosphoric Acid Catalysis; Povarov
Cycloaddition; Schiff Bases
The electronic and structural features of the ferrocene
moiety endow its derivatives with peculiar physico-
chemical
properties.
Ferrocene-containing
compounds are increasingly important structures,
instrumental to different fields, ranging from
medicinal chemistry and material science to synthetic
organic chemistry.[1,2]
Combining our experitises in ferrocene chemistry[3]
and in asymmetric catalysis mediated by chiral
Brønsted acids,[4] we set up to study asymmetric
reactions with ferrocenecarbaldehyde-derived N-aryl
imines 1. Our choice fell on the inverse-electron-
demand aza-Diels-Alder cycloaddition (Povarov
reaction)[5,6] with dienophiles 2, catalysed by
phosphoric acids 3,[7] which delivers 2-ferrocenyl-
1,2,3,4-tetrahydroquinolines 4 (Scheme 1). This work
was motivated by the combination of two elements:
Scheme 1. Chiral Brønsted acid 3 catalyzed Povarov
reactions of ferrocenecarbaldehyde-derived imines 1.
An unexpected yet remarkable result that has
emerged from this study is a new and exceedingly
efficient protocol for two and three component (2C
and 3C) Povarov reactions with benzyl N-
vinylcarbamate 2a.[10] Products 4 were obtained with
very high enantioenrichment (≥96% ee) in all cases.
1
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
More importantly, by slightly forcing the reaction
conditions the catalyst loading in the 2C version
could be lowered to 10-20 p.p.m. values, with only a
small erosion in enantioselectivity. This is a relevant
result considering the notoriously low turnover
numbers of organocatalytic reactions.[11] Only a small
Table 1. Optimization of catalysts and reaction conditions
in the Povarov reaction between imine 1a and N-vinyl
carbamate 2a. Representative results.a)
number
of
works
demonstrated
high
enantioselectivities and yields at catalyst loadings
lower than 100 p.p.m.[12] None of these has involved
a phosphoric acid as catalyst. In fact, the turnover
numbers of up to ca. 105 achieved in this reaction are
not only unprecedented for phosphoric acid catalysts,
but also approach the lower limits of the current
literature describing organocatalytic asymmetric
reactions.[12b] It is worth stressing that a relatively
simple and commercially available structure is used
as catalyst, and that the reaction at such low loadings
is not limited to ferrocene substrates, but could be
applied to imines derived from different
arylaldehydes.
Entry
Cat. 3 (mol%) Solvent Conv. (%)b) ee
(%)c)
93
1
2
3
4
5
6
7
3a (10)
3b (10)
3c (10)
3d (10)
3a (10)
3c (10)
3a (10)
3c (10)
3a (0.1)
3c (0.1)
CH2Cl2 21
CH2Cl2 18
CH2Cl2 10
CH2Cl2 <10
toluene >95
toluene >95
87
98
89
96
96
93
90
97
>99
We started this study by reacting imine 1a with
benzyl N-vinylcarbamate 2a, in the presence of
BINOL-derived chiral phosphoric acid catalysts 3 at
10 mol% loading (Table 1). Although the first
attempts using dichloromethane as solvent and 2
hours reaction time[10a,b] gave only poor conversion to
THF
THF
toluene 90
94
92
8
9d)
10d)
toluene >95
the
desired
tetrahydroquinoline
4a,
enantioselectivities were good with most catalysts
tested (entries 1-4). In these as well as in the
following experiments, the 2,4-cis-diastereoisomeric
product 4a was exclusively obtained, as expected.[10]
From this preliminary catalyst screening, the 4-
nitrophenyl and the 2,4,6-tri-isopropylphenyl
derivatives 3a and 3c ((R)-TRIP) were identified as
the most promising structures, and were selected for
further studies. A simple solvent switch from
dichloromethane to toluene (entries 5,6) allowed to
increase considerably the conversion of the reaction,
providing better results also compared to other
reaction media such as THF (entries 7,8). At this
point, we tried to lower the catalyst loading. As
shown in entries 9 and 10, even a loading of 0.1
mol% allowed to produce the product 4a with
optimal results, when the reaction time was increased
to 6 h. Under these conditions, catalyst 3c gave
slightly better results, furnishing 4a in nearly
enantiopure form.
a)
Conditions: imine 1a (0.05 mmol), N-vinylcarbamate 2a
b)
(0.06 mmol), catalyst 3, solvent (200 μL), RT, 2 h.
Determined by H NMR on the crude mixture. A single
cis-4a stereoisomer was observed in all cases.
Determined by chiral stationary phase HPLC.
reaction time.
1
c)
d)
6 h
Despite these optimal results achieved with imine
1a, when we moved to study reactions with imines
derived from electron poor anilines we found these
were not giving clean reaction profiles. As
exemplified in Scheme 2 for the 4-bromo and 4-
fluoroaniline derived substrates 1b,c, considerable
(>25%) amounts of co-products 4’b and 4’c formed.
These adducts 4’, observed as diastereomeric
mixtures, were the result of the interruption[4e,13] of
the Povarov reactions by the aniline, acting as an
external nucleophile on the intermediate A (see
pathway (b) vs pathway (a) in Scheme 2).[14] As the
only source of aniline could be the hydrolysis of the
imines 1, we reasoned that drying agents could avoid
this process. Indeed, performing the reaction in the
Scheme 2. Povarov cycloaddition reaction of imines 1b,c
(pathway (a)) giving 4b and 4c vs interrupted Povarov
reaction (pathway (b)) leading to 4’b and 4’c.
presence of activated 4 Å molecular sieves allowed
the nearly exclusive obtainment of the desired
cycloadducts 4 (Scheme 2). MgSO4 as drying agent
was instead less effective.
We thus applied these newly developed conditions
to few ferrocenecarbaldehyde imines 1a-i derived
from anilines featuring different electronic properties
2
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
Table 2. Catalytic asymmetric two component (method A) and three component (method B) Povarov reactions between
benzyl N-vinylcarbamate 2a and ferrocenecarbaldehyde imines 1a-i catalysed by 3c.
Method A (2C)a)
Method B (3C)b)
Yield (%)d) ee (%)e)
Entry
1
R1
R2
R3
4c)
Yield (%)d)
ee (%)e)
1
2
3
4
5
6
7
8
OMe
Br
F
Me
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
99
96
86
92
>99
>99
>99
>99
>99
99
99
80
95
92
80
88
>99
>99
>99
>99
>99
99
1a
1b
1c
1d
1e
1f
1g
1h
1i
4a
4b
4c
4d
4e
H
83
OMe
Cl
H
4ff)
4gg)
4h
4i
98
90h)
75k)
50k)
99i)/99j)
98
90h)
52k,l)
60k,l)
99i)/>99j)
97
9
H
-(CH)4-
98
96
a)
Conditions (method A, 2C): imine 1a-f (0.20 mmol), N-vinylcarbamate 2a (0.24 mmol), catalyst 3c (0.1 mol%),
activated 4 Å MS (60 mg), toluene (800 μL), RT, 6 h. b) Conditions (method B, 3C): ferrocenecarbaldehyde (0.20 mmol),
aniline (0.20 mmol), catalyst 3c (0.10 mol%), activated 4 Å MS (60 mg), toluene (800 μL), RT, 1 h, then N-
vinylcarbamate 2a (0.24 mmol), RT, 5 h. c) A single cis-diastereoisomer 4 was observed in the crude mixtures by 1H NMR.
d)
e)
f)
Isolated yield after chromatography on silica gel. Determined by chiral stationary phase HPLC. The 6,7-dimethoxy
g)
regioisomer of 4f was selectively obtained. Mixture of 7-chloro and 5-chloro 4g regioisomers (56:44 favouring 5-Cl
regioisomer). h) Combined yield of the two 4g regioisomers. i) 7-Cl 4g isomer. j) 5-Cl 4g isomer. k) 18 h reaction time. l) 2.0
mol% catalyst 3c was used.
(Table 2, method A). Products 4a-e derived from
para-substituted/unsubstituted anilines were
The corresponding products 4h and 4i were afforded
in moderate yields and very good enantioselectivities
(entries 8,9).
produced as single cis-diastereoisomers and in nearly
enantiopure form in all cases, demonstrating the
outstanding efficiency of catalyst 3c in imparting
enantioselectivity to this reaction (entries 1-5). The
absolute and relative configuration of cycloadduct 4b
was determined as S,S by single crystal X-ray
diffraction (Figure 1),[15] and is fully consistent with
previous chiral phosphoric acid catalysed Povarov
reactions.[4b,d-f,10] The configuration of all products 4
(and 5-8, vide infra) was assigned by analogy.
Reactions with meta substituted anilines were then
explored. While the 3,4-dimethoxyaniline derived
substrate 1f afforded exclusively the 6,7-dimethoxy
regioisomer 4f, the 3-chloro substituted substrate 1g
gave a nearly equimolar mixture of the 5-chloro and
7-chloro 4g regioisomers, in line with previous
studies.[10b] Yields and enantioselectivites were very
good in both cases (entries 6,7). Two ortho-
substituted aniline derived substrates 1h and 1i
derived from 2-methylaniline and 1-naphthylamine,
respectively, were then tested in the reaction.
Although requiring longer reaction times, also these
more challenging imines reacted well in the reaction.
Figure 1. X-Ray structure of compound 4b.
Moving to develop the 3C version of the reaction,
we had to face again the issue of co-product 4’
formation when electron poor anilines were
employed (see Scheme 2), which occurred even in the
presence of molecular sieves. In more detail, if the
3
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
imine was not quantitively formed before the addition
of N-vinylcarbamate 2a to the reaction mixture,
residual aniline interfered with the cycloaddition
reaction resulting in substantial amounts of co-
product 4’. Ultimately, we found that leaving the
aniline and ferrocenecarbaldehyde condensing in the
presence of the catalyst 3c and 4 Å molecular sieves
for 1 hour before the addition of the dienophile 2a,
was sufficient to avoid the formation of undesired
adducts 4’. Accordingly, this optimised protocol for
the 3C reaction (method B, Table 2) was applied to
the same substrates previously employed in the 2C
version. Most substrates reacted very well, giving
results comparable to the 2C version of the reaction
(entries 1-7). A higher catalyst loading (2 mol%) and
longer reaction times were instead necessary to
achieve satisfactory results in the reactions of ortho-
substituted aniline derived substrates 1h and 1i
(entries 8,9).
We then verified the applicability of imine 1a in
other asymmetric Povarov reactions, by reacting it
with four different dienophiles 2b-e, known to be
competent in chiral phosphoric acid catalysed
Povarov reactions.[4b,e,f,10b] As shown in Scheme 3,
product 5 derived from benzyl (E)-prop-1-en-1-
ylcarbamate 2b was obtained with good results, using
conditions similar to the ones employed for 2a. A
higher catalyst loading (1 mol% instead of 0.1 mol%)
and longer reaction times were necessary, presumably
due to the higher steric hindrance of enecarbamate 2b
compared to unsubstituted 2a. As expected,
dienophile 2c (a dienecarbamate reacting at the
vinylogous double bond)[4b,f] required instead a
different catalyst (3e) to afford the cycloadduct 6
with good enantioselectivity. Moving to heteroarene
activated dienophiles, 2-vinylindole 2d reacted very
well under conditions related to the ones used for 2a
and 2b, using just 1 mol% of catalyst 3c at 40 °C. In
contrast, 3-vinylindole 2e gave initially disappointing
results. This very electron rich dienophile is not only
prone to acid promoted degradation, but also feature a
tendency towards the formation of piperidines
resulting from interrupted Povarov reaction. In line
with our previous work with this dienophile,[4e] good
results were ultimately achieved by using more
diluted conditions in a coordinating solvent (THF),
and adding slowly a solution of 2e in THF to the
reaction mixture (by syringe pump).
Prompted by the outstanding performance
displayed by catalyst 3c in the 2C reaction between
imine 1a and N-vinyl carbamate 2a (≥99% ee and
quantitative yield in 6 h using 0.10 mol% 3c, Table 1,
entry 10), we decided to challenge the system to
ascertain the lowest catalyst loading reachable in this
reaction (Table 3). A decrease in the amount of
catalyst 3c from 0.1 mol% to 0.01 mol% gave still
fully satisfactory results, even if the reaction time had
to be increased from 6 to 24 h (entries 1 and 2). A
further decrease to 0.001 mol% (10 p.p.m.) worsened
the conversion, even at prolonged reaction times
(entry 3). Rising the reaction temperature to 40 °C
restored a moderate conversion value, accompanied
by a slightly lower but still very high enantiomeric
excess (entry 4). Under these conditions, we tested
some drying agents, standard additives in phosphoric
acid catalysed reactions.[16] As shown in entry 5, the
presence of 4 Å molecular sieves was surprisingly
detrimental to catalyst activity with this little amount
of catalyst.[17] In contrast, dry MgSO4 gave a small
yet important improvement (entry 6), compared to the
reaction performed in its absence (entry 4).
Scheme 3. Catalytic enantioselective Povarov reactions between imine 1a and dienophiles 2b-e.
4
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
Table 3. Representative results on the catalytic asymmetric Povarov reactions between benzyl N-vinylcarbamate 2a and
ferrocenecarbaldehyde imine 1a catalysed by 3c at low catalyst loading.a)
Entry
3c mol%
3c p.p.m.
Additive
T (°C)
t (h)
Conversion
(%)b)
ee (%)c)
1d)
2
3
4
5
6
7
8
9
0.1
0.01
1’000
100
10
10
10
10
10
10
20
-
-
-
-
RT
RT
RT
40
40
40
60
60
60
60
6
>95
91
29
56
21
70
85
39
93
22
>99
>99
95
96
n.d.
96
94
n.d.
96
24
120
48
48
48
60
96
60
60
0.001
0.001
0.001
0.001
0.001
0.001
0.002
0.0001
4 Å MS
MgSO4
MgSO4
4 Å MS
MgSO4
MgSO4
10
1
82
a) Conditions: imine 1a (0.20 mmol), N-vinylcarbamate 2a (0.24 mmol), catalyst 3c, (additive (60 mg)), solvent (800 μL).
b) Determined by 1H NMR on the crude mixture. A single cis-4a stereoisomer was observed in all cases. c) Determined by
chiral stationary phase HPLC. d) Reaction performed on 0.05 mmol scale (Table 1, entry 10).
Ultimately, satisfactory conversion accompanied by
very good enantioselectivity could be achieved at this
10 p.p.m. loading by increasing the reaction
temperature to 60 °C, and the reaction time to 60 h
(entry 7). Under these conditions, the negative effect
displayed by molecular sieves was confirmed (entry
8). Conversely, slightly higher conversion and
enantioselectivity was achieved using 20 p.p.m.
loading with MgSO4 (entry 9). It is worth stressing
that these reactions were performed using reagent
grade toluene, as drying or degassing the solvent did
rings. Such type of imines has been reported to react
very well with dienophile 2a under the action of
phosphoric acid catalysts related to 3c. These
reactions were performed in dichloromethane as
solvent, and the imines were prepared in situ via a 3C
protocol.[10] The lowest catalyst loading attainable has
been 0.5 mol% (5’000 p.p.m.). Our experiments,
performed under the conditions we optimised for 1a,
gave instead good results even at 20 p.p.m. loading
(Scheme 5).[18] Cycloadducts 4j-l were in fact
obtained
with
very
good
yields
and
not give any beneficial effect on the reaction outcome. enantioselectivities in all three cases. Thus, the
A further decrease in the loading to 0.0001 mol% (1
p.p.m.) was unfortunately not practical (entry 10).
The conditions of Table 3, entry 9 were enough
robust to be successfully applied on a preparative
scale (5 mmol) reaction (Scheme 4). In fact, the
reaction proved to be very tolerant to this 25 × scale
up, providing product 4a in very good yield and
enantioselectivity. Remarkably, as low as 0.075 mg
of catalyst 3c (added from a mother solution) were
sufficient to produce 1.99 g of product 4a in 97% ee.
efficacy of this low loading protocol is not restricted
to ferrocenecarbaldehyde imine 1a. It can also be
concluded that the high catalyst efficiency displayed
by catalyst 3c in these Povarov reactions is not due to
the ferrocenyl moiety of 1a, but rather to the specific
conditions we have used in the reaction.
Scheme 5. Povarov reaction of arylaldehyde imines 1j-l
with N-vinyl carbamate 2a catalysed by 3c at 20 p.p.m.
loading. Cycloadducts 4j-l were obtained as single cis-
diastereoisomers.
Scheme 4. Preparative scale Povarov reaction of
ferrocenecarbaldehyde imine 1a with N-vinyl
carbamate 2a catalysed by 3c at 20 p.p.m. loading.
In conclusion, we have developed catalytic
enantioselective Povarov reactions of N-aryl
ferrocenecarbaldehyde imines 1. The reactions
furnished highly enantioenriched 2-ferrocenyl-
1,2,3,4-tetrahydroquinoline compounds 4-8, of
potential interest due to the combination of the
properties of the tetrahydroquinoline and the
ferrocenyl groups. This study demonstrates that the
At this stage, we wondered if the efficiency of this
reaction in terms of catalyst loading, unprecedented
in the frame of phosphoric acid catalysis, had to be
ascribed to the peculiar stereoelectronic properties of
the ferrocene moiety of substrate 1a. We thus
engaged in the reaction other N-4-methoxyphenyl
aldimines 1j-l derived from arylaldehydes bearing
electron releasing or electron withdrawing aromatic
5
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
stereoelectronic properties of ferrocenyl imines 1 do
not preclude their engagement in enantioselective
Brønsted acid catalysis. An efficient protocol for the
Povarov reaction with benzyl N-vinyl carbamate 2a
was developed, enabling the obtainment of the
products with ≥96% ee in all cases. With some
specific substrates, it was possible to further optimise
the reaction reaching a record low catalyst loading of
10-20 p.p.m. in the reactions.
(Eds.: L.-X. Dai, X.-L. Hou), Wiley-VCH, Weinheim,
2010.
[2] For specific overviews on biologically relevant
ferrocene compounds, see: a) E. A. Hillard, A.
Vessières, G. Jaouen in Topics in Organometallic
Chemistry, Vol. 32 (Eds.: G. Jaouen, N. Metzler-Nolte),
Springer-Verlag, Berlin-Heidelberg 2010, pp. 81–118;
b) C. Biot, D. Dive in Topics in Organometallic
Chemistry, Vol. 32 (Eds.: G. Jaouen, N. Metzler-Nolte),
Springer-Verlag, Berlin-Heidelberg 2010, pp. 155–194;
c) M. F. R. Fouda, M. M. Abd-Elzaher, R. A.
Abdelsamaia, A. A. Labib, Appl. Organometal. Chem.
2007, 21, 613–625; d) M. Patra, G. Gasser, Nat. Rev.
Chem. 2017, 1, article number 0066.
Experimental Section
Preparative catalytic asymmetric Povarov reaction of
1-ferrocenyl-N-(4-methoxyphenyl)methanimine 1a with
benzyl N-vinylcarbamate 2a at 20 p.p.m. catalyst
loading.
[3] a) A. Minić, D. Stevanović, I. Damljanović, A. Pejović,
M. Vukićević, G. A. Bogdanović, N. S. Radulović, R.
D. Vukićević, RSC Adv. 2015, 5, 24915–24919; b) I.
Damljanović, D. Stevanović, A. Pejović, D. Ilić, M.
Živković, J. Jovanović, M. Vukićević, G. A.
Bogdanović, N. S. Radulović, R. D. Vukićević, RSC
Adv. 2014, 4, 43792–43799; c) A. Pejović, I.
Damljanović, D. Stevanović, M. Vukićević, S. B.
Novaković, G. A. Bogdanović, N. S. Radulović, R. D.
Vukićević, Polyhedron 2012, 31, 789–795; d) A.
Pejović, M. S. Denić, D. Stevanović, I. Damljanović, M.
Vukićević, K. Kostova, M. Tavlinova-Kirilova, P.
Randjelović, N. M. Stojanović, G. A. Bogdanović, P.
Blagojević, M. D’hooghe, N. S. Radulović, R. D.
Vukićević, Eur. J. Med. Chem. 2014, 83, 57–73; e) N.
S. Radulović, M. Z. Mladenović, Z. Stojanović-Radić,
G. A. Bogdanović, D. Stevanović, R. D. Vukićević,
Mol. Divers. 2014, 18, 497–510; f) A. Minić, D.
Stevanović, M. Vukićević, G. A. Bogdanović, M.
D’hooghe, N. S. Radulović, R. D. Vukićević,
Tetrahedron 2017, 73, 6268-6274.
To a Schlenk tube equipped with a magnetic stirring bar,
dry MgSO4 (1.50 g) was added and thermally activated
(heat gun) under vacuum for ca. 10 minutes and then
allowed to cool to room temperature. After cooling, the
Schlenk tube was filled with nitrogen. Ferrocenyl-N-(4-
methoxyphenyl)methanimine 1a (1.59 g, 5.0 mmol) and
toluene (20 mL) were added under nitrogen atmosphere,
followed by 20 μL of a 5 mM mother solution of (R)-TRIP
3c in toluene (corresponding to 0.075 mg, 1.0×10-4 mmol,
20 p.p.m.: this solution was prepared dissolving 3.8 mg of
3c in 1.0 mL of toluene). Benzyl N-vinylcarbamate 2a
(1.06 g, 6.0 mmol) was then added, the reaction mixture
was heated to 60 °C and stirred at this temperature under
nitrogen atmosphere. After 65 h, the mixture was filtered
through a plug of silica gel and the plug washed with Et2O
(4×). After the evaporation of the solvents, the residue was
analyzed by 1H NMR spectroscopy to determine the
diastereomeric ratio of the product (a single cis-
diastereoisomer was detected). Finally, the crude product
was purified by column chromatography (SiO2; n-hexane-
EtOAc 9:1). 1.99 g (4.0 mmol, 80% yield) Of benzyl
((2S,4S)-2-ferrocenyl-6-methoxy-1,2,3,4-
tetrahydroquinolin-4-yl)carbamate 4a were thus obtained
as a yellow solid. The ee of the product was determined by
HPLC using a Chiralpak AD-H column (n-hexane/i-PrOH
80:20, flow-rate 0.75 mL/min, tmaj= 32.5 min, tmin= 36.6
min, ee 97%).
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Acknowledgements
We acknowledge financial support by the University of Bologna
(RFO program). Donation of chemicals from Dr. Reddy’s
Chirotech Technology Centre (Cambridge, U.K.) is gratefully
acknowledged. We thank Prof. Carmen Nájera for a gift of (R)-
BINOL. D.S. is grateful for a postdoctoral fellowship from the
Ministry of Education, Science and Technological Development
of the Republic of Serbia (Grant No. 451-03-1026/2016-14).
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Crystallographic Data Centre.
7
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
[16] L. Hong, W. Sun, D. Yang, G. Li, R. Wang, Chem.
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also verified that the magnesium salt of catalyst 3c is
not efficient in the promotion of these reactions,
although we could not reach a decisive conclusion (see
Supporting Information). We thank two anonymous
reviewers for these useful suggestions.
[17] Molecular sieves contain alkaline and alkaline earth
metals. As suggested by a reviewer, it can be
speculated that at very low catalyst loadings molecular
sieves (in large excess compared to the catalyst)
convert the acidic catalyst to metal phosphate species.
Calcium phosphates derived from catalysts 3 are
known to be inefficient in the promotion of Povarov
reactions.[10b] Prompted by another reviewer, we have
[18] Compared to the reaction with 1a, with imines 1j-l it
proved advantageous to perform the reactions at 40 °C,
in terms of enantiomeric excess.
8
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10.1002/adsc.201701484
Advanced Synthesis & Catalysis
COMMUNICATION
Catalytic Enantioselective Povarov Reactions of
Ferrocenecarbaldehyde-Derived Imines – Brønsted
Acid Catalysis at Parts-Per-Million Level Loading
Adv. Synth. Catal. Year, Volume, Page – Page
Dragana Stevanović, Giulio Bertuzzi, Andrea
Mazzanti, Mariafrancesca Fochi,* Luca Bernardi*
9
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