Asymmetric formal carbonyl-ene reactions of formaldehyde tert -butyl hydrazone with α-keto esters: Dual activation by bis-urea catalysts

Article abstract of DOI:10.1021/ja305209w

The dual activation of α-keto esters and formaldehyde tert-butyl hydrazone by BINAM-derived bis-ureas is the key to achieve high reactivity and excellent enantioselectivities in nucleophilic addition (formal carbonyl-ene reaction) to functionalized tertiary carbinols. Ensuing high-yielding diazene-to-aldehyde tranformations and subsequent derivatizations provides a direct entry to a variety of densely functionalized products.

Full text of DOI:10.1021/ja305209w

Communication
pubs.acs.org/JACS
Asymmetric Formal Carbonyl-Ene Reactions of Formaldehyde tert-
Butyl Hydrazone with α‑Keto Esters: Dual Activation by Bis-urea
Catalysts
†
‡
‡
†
,‡
́
Ana Crespo-Pena, David Monge, Eloísa Martín-Zamora, Eleuterio Alvarez, Rosario Fernandez,*
́
̃
and Jose M. Lassaletta*,†
†Instituto Investigaciones Químicas (CSIC-US), C/Amer
‡Departamento de Química Organ
́
́
ico Vespucio, 49, 41092 Sevilla, Spain
́
ica, University of Seville, C/Prof. García Gonzalez, 1, 41012 Sevilla, Spain
́
S
* Supporting Information
side reactions, decomposition, dimerization, or catalyst
deactivation.8 The mild nature of the organocatalytic activation
of electrophilic compounds, however, appears to be more
appropriate for these reactions, and applications have been
developed for the addition to imines9 and Michael acceptors.10
Despite intensive efforts, however, we failed to develop
asymmetric organocatalytic additions to carbonyl compounds.
Baldwin et al. had previously reported on the use of azo anions
from bulky monoalkyl hydrazones 2 as acyl anion equivalents
(eq 2).11 Additionally, neutral monoalkyl hydrazones have
shown reactivity in thermal ene reactions with methyl acrylate
and acrylonitrile,12 but, to the best of our knowledge, these
reagents have never been used in nucleophilic additions
(formally carbonyl-ene reactions) to carbonyl compounds (eq
3). Considering that the presence of the NH group offers
additional opportunities for interaction with an organocatalyst,
we decided to explore the reactivity of formaldehyde tert-butyl
hydrazone 3 in this context. In this paper we wish to disclose
our findings on the reaction with α-keto esters 4.
ABSTRACT: The dual activation of α-keto esters and
formaldehyde tert-butyl hydrazone by BINAM-derived bis-
ureas is the key to achieve high reactivity and excellent
enantioselectivities in nucleophilic addition (formal
carbonyl-ene reaction) to functionalized tertiary carbinols.
Ensuing high-yielding diazene-to-aldehyde tranformations
and subsequent derivatizations provides a direct entry to a
variety of densely functionalized products.
he asymmetric 1,2-addition of acyl anion equivalents to
Tcarbonyl compounds is a powerful synthetic tool that
provides direct access to functionalized carbinols.1 Most
organocatalyzed nucleophilic acylations are mediated by N-
heterocyclic carbene catalysts,2 but this strategy fails in the
formaldehyde case due to self-condensations (the formose
reaction).3 On the other hand, the marked aza-enamine
(nucleophilic) character of formaldehyde N,N-dialkyl hydra-
zones 1 has been exploited for the functionalization of diverse
electrophiles,4 including carbonyl compounds such as alde-
hydes,5 trifluoromethyl ketones,6 and α-keto esters7 (Scheme 1,
eq 1). The development of catalytic asymmetric approaches
based on chiral Lewis acids is problematic because of the
tendency of these reagents 1 to bind acidic metals and undergo
Scheme 2
Scheme 1. Hydrazone-Based Formyl Anion Equivalents
Preliminary experiments were performed with commercially
available ethyl phenylglyoxylate 4a (Scheme 2). At room
temperature, this substrate smoothly reacted with 3 under
thermal conditions to afford the α-hydroxy ester 5a at a
reasonable rate (43% conversion after 3 h in toluene; 78% after
24 h, Table 1, entry 1), while addition of 10 mol% of N,N′-
bis[3,5-bis(trifluoromethyl)phenyl] thiourea I slightly acceler-
ated the reaction (reaction finished in 9 h, entry 2), showing
that the background reaction could interfere with the catalytic
version. Fortunately, cooling to −15 °C practically inhibited the
uncatalyzed reaction (<5% conversion after 24 h, entry 3),
while a significant acceleration by the catalyst I was observed at
this temperature (reaction complete in 10 h, entry 4), thereby
Received: May 29, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja305209w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Thermal and Catalytic Reaction of 3 with Keto
Ester 4a
Table 2. Catalytic Additions of 3 to α-Keto Esters 4a−q
a
b
c
entry
cat.
t (h)
T (°C)
yield (%)
ee (%)
1
2
-
I
24
9
rt
78
90
<5
95
99
-
-
-
-
rt
3
-
24
10
72
72
72
72
78
42
-15
-15
-15
-15
-15
-15
-30
-30
4
I
t
T
yield
ee
(%)
b
c
d
entry
4
X
cat.
(h)
(°C) (%)
5
5
II
III
IV
V
II
II
78
e
f
d
6
55
24
1
2
3
4
4b
4c
4c
4d
-
IV
II
72
72
-15
-15
-30
-15
89
5b
5c
5c
5d
49
82
84
72
d
7
99
74
4-Me
4-Me
4-OMe
96
91
67
e
f
8
51
22
II
96
d
9
96
97
90
IV
144
dg
,
10
91
(>99)
91
a
5
6
7
8
9
4e
4f
4f
4f
4g
2-OMe
4-CN
4-CN
4-CN
2-Br
IV
II
144
7
-15
-45
-45
-45
-45
81
99
95
95
96
5e
5f
5f
5f
5g
Reactions performed at 0.5 mmol scale using 10 mol% catalyst
b
loading unless otherwise stated. Isolated yield after column
92
c
d
e
chromatography. Determined by HPLC. Major enantiomer eluted
II
10
12
15
94
e
first. Yield estimated by 1H NMR of the crude reaction mixture.
f
II
86
f
g
Major enantiomer eluted second. Reaction performed at 4 mmol
IV
91
(>99)
91
scale.
10
4h
2-Cl
IV
15
-45
94
5h
(>99)
>99
11
12
13
14
15
16
17
18
19
20
21
4i
4i
2-F
2-F
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
8
16
19
4
-45
-45
-45
-45
-45
-45
-45
-45
-45
-45
-30
99
97
94
92
93
94
95
99
98
99
99
5i
5i
e
96
f
4i
2-F
5i
94
4j
2,4-F2
2,4-F2
2,4-F2
2,5-F2
4-Br,2-F
5-Br,2-F
3,4-Cl2
-
5j
98
e
4j
10
14
3
5j
98
f
4j
5j
90
Figure 1. BINAM-derived bis-ureas and bis-thioureas.
4k
4l
5k
5l
97
>99
97
5
opening opportunities for the development of an asymmetric
catalytic version. After a screening of available organocatalysts,
(R)-BINAM-derived bis-urea II (BINAM = 2,2′-diamino-1,1′-
binaphthalene, Figure 1) emerged as the most promising
catalyst.13 Thus, addition of II (10 mol%) to the model reaction
in toluene at −15 °C led to the isolation of enantioenriched 5a
in a nearly quantitative yield and 78% ee (entry 5). It is
noteworthy that the bis-thiourea analogue (R)-III, although
reported to be a superior catalyst in related reactions,13a,14
proved to be a less efficient one in this case [55% versus 100%
conversion after 72 h, respectively (entry 6)], leading to the
product 5a with a moderate 24% ee and with the opposite sense
of enantioselection. This anomalous behavior was also observed
for the partially hydrogenated bis-urea and bis-thiourea
analogues IV and V (entries 7 and 8), confirming that the
observed phenomenon cannot be taken as an isolated case.15
Using the best catalysts II, the enantioselectivity was further
improved to 90% ee by performing the reaction at −30 °C
(entry 9). Moreover, the reaction carried out at 4 mmol scale
proved to be even faster, reaching completion in 42 h and
affording the product 5a in 97% yield with essentially the same
ee (entry 10).16
The scope of the reaction was then explored with a range of
α-keto esters 4 (Table 2). Ethyl pyruvate 4b was used as a
representative of aliphatic substrates. Though the observed
reactivity is similar to that observed for 4a, a poorer 49% ee was
reached, using in this case bis-urea IV as the best catalyst (entry
1). Therefore, we focused on aromatic and heteroaromatic
substrates 4c−q with several substitution patterns. The
collected data show that the expected products 5c−q (Chart
1) were obtained in nearly quantitative yields and high
enantioselectivities in most cases, either using catalyst II
(5a,c,f,p) or IV (5d,e,g−o,q) as the best option. As expected,
the reaction rates correlate with the electronic properties of the
4m
4n
4o
3
5m
5n
5o
9
89
72
90
(>99)
88
22
23
4p
4q
-
-
II
72
96
-30
-30
91
93
5p
5q
IV
93
a
Reactions performed at 0.5 mmol scale using 10 mol% catalyst
loading. Isolated yield after column chromatography. Determined by
HPLC on chiral stationary phases. In parentheses, ee after a single
crystallization. GC yield. Catalyst loading 5 mol%. Catalyst loading
2 mol%.
b
c
d
e
f
aryl group: electron-rich derivatives 4c−e required long
reaction times for completion (entries 2−5). On the other
hand, substrates 4f−n carrying electron-withdrawing groups
reacted much faster, reaching completion in shorter times, even
at −45 °C (entries 6−20). The high reactivity shown in these
cases made it possible to reduce the catalyst loading to 5 mol%
without compromising the selectivity nor the chemical yield, as
shown for representative cases 4f, 4i, and 4j (entries 7, 13, and
15). Further reduction of the catalyst loading to 2 mol% still
gave good results for 4i (entry 13), but the enantioselectivity
dropped slightly for 4f and 4j (entries 8 and 16). It is
noteworthy that nearly perfect enantioselectivities were
observed for ortho-fluorinated substrates 4i−m, giving practi-
cally enantiopure derivatives 5i−m (98 to >99% ee). Finally, 2-
naphthyl, 2-thienyl, and 8-isoquinolyl glyoxylates 4o−q were
used as representatives of bicyclic and heteroaromatic
substrates, affording also the expected products 5o−q in
good yields and high enantioselectivities for reactions carried
out at −30 °C (entries 21−23).
Some of the products 5 proved to be fairly crystalline, and
this circumstance was exploited to obtain essentially pure
B
dx.doi.org/10.1021/ja305209w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Chart 1. Structures of Products 5a,c−q
Scheme 3. Proposed Catalytic Cycle and Stereochemical
Model
enantiomers of the p-anisyl (5d), o-bromo (5g), o-chloro (5h),
and 2-naphthyl (5o) derivatives after a single crystallization
(entries 4, 9, 10, and 21). In the case of (R)-5h, the available X-
ray-quality crystals were used to determine the absolute
configuration of the newly created stereogenic center (see
Supporting Information).
Figure 2. Hybrid thiourea−urea bifunctional catalyst VI.
depicted model A suggests the participation of one of the acidic
ortho CH bonds of the bis-(CF3)C6H3 groups in a H-bond
network that places the bulkier aromatic group of the substrate
away from the more hindered inner region of the catalyst. In
agreement with this hypothesis, the chemical shifts of these
The divergent stereochemical results obtained with bis-
thiourea catalysts III/V and bis-urea analogues II/IV suggest
that different activation modes are involved in both cases.
Considering the close structural similarity between both types
of catalysts, the higher hydrogen donor−acceptor capability of
the oxygen in the carbonyl group of catalysts II/IV appears as
one of the fundamental (and obvious) differences.17 Con-
sequently, it was suggested that one of the urea carbonyl groups
in these catalysts might serve as a H-bond acceptor for the
hydrazone NH group, providing an additional interaction that
could hardly be effected by bis-thiourea derivatives III/V.18
This hypothesis led to the proposal of a stereochemical model
where the second urea moiety activates the carbonyl substrate 4
in a ternary complex A, which is preorganized for the attack of
the azomethine carbon to the Re face of the ketone carbonyl,
leading to a zwitterionic intermediate B that releases the
product 5a and the catalyst II or IV (Scheme 3).
1
protons in the H NMR spectrum of II are affected by the
addition of increasing amounts of 4a.19 Thus, after an initial
upfield shift observed upon addition of 0.25 equiv of 4a,20 the
chemical shitfs of these protons were progressively shifted
downfield upon further addition of 4a (Δδ up to 0.1 ppm at a
1:4 II/4a ratio).
Further support for the proposed dual mode of activation
was collected from hybrid thiourea−urea catalyst VI (Figure 2).
Assuming that just one good H-bond acceptor moiety is
required to activate the hydrazone 3, this hybrid catalyst VI
should behave as II/IV, not as III/V. In fact, the
enantioselectivity reached with this catalyst matched that
obtained with the bis-urea II, affording the product with
similar enantiomeric excess (88% ee at −30 °C) and in a
slightly shorter reaction time of 64 h, which accounts for the
slighty better H-bond donor properties of the thiourea moiety.
To demonstrate the announced formyl anion equivalence of
reagent 3, representative products 5a,d,i,o,p were transformed
into the corresponding aldehydes 6a,d,i,o,p via a tautomeriza-
tion/hydrolysis sequence efficiently accomplished by simple
treatment with HCl in a biphasic H2O/Et2O medium (Scheme
4).
The proposed formation of an NH···O hydrogen bond is
expected to increase the electron density in the conjugated
hydrazone system, so the nucleophilicity of the azomethine
carbon should be enhanced. This bifunctional mode of
activation would therefore explain the better catalytic activity
and selectivity of II and IV as the result of the cooperative
interactions shown and the highly ordered reactive complex
resulting from the dual activation. Additional experimental
support for this model was collected from NMR experiments.
Crude aldehydes 6 did not resist chromatographic
purification but were isolated with a high degree of purity
1
Thus, H NMR spectra recorded for 3 in the presence of
1
increasing amounts of catalyst II show the azomethine protons
shifted upfield (Δδ up to −0.07 ppm at a 1:1 ratio, see
Supporting Information for details), as expected from a higher
electron density at the azomethine carbon. Additionally, the
(estimated by H NMR). Moreover, treatment of these crude
products with Bu4NBH4 afforded diols 7a,d,i,o,p in good
overall yields, and the structure of crystalline derivative (R)-7p
supported a uniform stereochemical pathway. Additionally,
C
dx.doi.org/10.1021/ja305209w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(grants 2008/FQM-3833 and 2009/FQM-4537) for financial
support. A.C.-P. thanks CSIC for a JAE predoctoral fellowship.
D.M. acknowledges a “Juan de la Cierva” contract.
Scheme 4. Functional Group Transformations from 5
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data; CIF data for
(R)-5h and (R)-7p. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
(16) Catalyst II (302 mg, 95%) could also be recovered after the
chromatographic purification.
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AUTHOR INFORMATION
Corresponding Author
ffernan@us.es; jmlassa@iiq.csic.es
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Dedicated to Prof. Miguel Angel Miranda on the occasion of
his 60th birthday. We thank the Spanish “Ministerio de Ciencia
■
(20) This initial upfield shift is attributed to the disruption caused by
the keto ester in the inter- and intramolecular H-bonding network. For
a closely related structure see: Holakovsky, R.; Pojarova,
́
M.; Dusek,
́
e Innovacion
́
” (grants CTQ2010-15297 and CTQ2010-14974),
M.; Cejka, J.; Císarova,
́
I. Acta Crystallogr. Sect. E 2011, 67, o384.
́
the European FEDER funds, and the Junta de Andalucia
D
dx.doi.org/10.1021/ja305209w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX