Evidence for an enol mechanism in a highly enantioselective Mannich-type reaction catalyzed by primary amine-thiourea

Article abstract of DOI:10.1002/anie.200800849

(Chemical Equation Presented) A tale of two mechanisms - enol versus enamine: Chiral primary amine-thiourea 1 catalyzes highly enantioselective Mannich-type addition of unmodified ketones to N-benzoylhydrazones (see scheme). The reaction does not require

Full text of DOI:10.1002/anie.200800849

Communications
DOI: 10.1002/anie.200800849
Organocatalysis
Evidence for an Enol Mechanism in a Highly Enantioselective
Mannich-Type Reaction Catalyzed by Primary Amine–Thiourea**
Denis A. Yalalov, Svetlana B. Tsogoeva,* Tatyana E. Shubina, Irina M. Martynova, and
Timothy Clark
Whereas impressive progress has been made in recent years in
developing highly enantioselective secondary and tertiary
amine–thiourea bifunctional organocatalysts for a diverse
range of reactions,[1,2] little work has yet been devoted to
developing primary amine–thiourea catalysis.[3] The use of
chiral primary amines as organocatalysts[4] possesses partic-
ular charm because of their known occurrence in the catalytic
Figure 1. Bifunctional amine–thiourea catalysts.
sites of several enzymes, such as type I aldolases, dehydra-
tases, and decarboxylases.[5] Recently, our group,[3a,c,e] as well
as Jacobsen and co-workers,[3b,d] reported the first successful
application of primary amine–thiourea organocatalysts to
nitro-Michael addition reactions. These findings also moti-
vated Ma and co-workers to develop a new primary amine–
thiourea organocatalyst for a similar Michael addition of
ketones to nitroalkenes.[3f]
The proven ability of primary amine–thioureas 1–3
(Figure 1)[3a,c,e] to catalyze the nitro-Michael reaction with
high enantioselectivity and the straightforward accessibility of
these thiourea–amines in a one-step synthesis from commer-
cially available reagents, as we reported earlier,[3d,e] prompted
us to also examine them for the Mannich reaction, which is
among the most powerful tools for preparing b-amino
carbonyl compounds.[6]
Herein we report, to the best of our knowledge, the first
chiral primary amine–thiourea catalyzed simple Mannich-
type addition of unmodified ketones to N-benzoylhydrazones,
which proceeds with good yields and high enantioselectivities
(up to 89% yield and > 99% ee). Additionally, we provide
some of the first computational evidence that the preferred
mechanism involves enol, rather than enamine intermediates.
out in toluene at room temperature in the presence of each
of the amine–thioureas (Table 1, entries 1–3). However,
amine–thioureas 1–3 gave inferior results with the selected
substrate (up to 47% yield and 45% ee with amine–thiourea
1, Table 1, entries 1–3). Additionally, the corresponding
N-PMP-protected a-imino ethyl glyoxylate 4 is not very
stable. We therefore sought other, readily available and more
stable substrates.
Our efforts focused on the reaction between acetone and
N-benzoylhydrazone 5 (Table 1, entries 4–6), which can be
stored for several months at room temperature and is readily
obtained from the condensation of ethyl glyoxylate and
benzhydrazide.[8]
N-Benzoylhydrazones have been used as substrates for
[8]
À
several C C bond-forming reactions; for example, the
allylation[8b] and Mannich-type reactions.[8a,c–e] Kobayashi
and co-workers have recently developed several metal-
containing Lewis acid assisted catalytic, and stoichiometric,
indirect stereoselective Mannich transformations of N-ben-
zoylhydrazones that utilize preformed silyl enolate.[8a,c–e] An
organocatalytic version of this reaction has not been pre-
viously reported, especially one in which unmodified ketones
To evaluate the catalytic efficiency of chiral amine– react with N-benzoylhydrazones.
thioureas 1–3, we first investigated the known addition of
acetone to N-PMP-protected a-imino ethyl glyoxylate
Table 1: Screening of amine–thioureas 1–3 for Mannich-type reactions.
(PMP = para-methoxyphenyl).[7] The reaction was carried
[*] Dr. D. A. Yalalov, Prof. Dr. S. B. Tsogoeva, Dr. I. M. Martynova
Department of Chemistry and Pharmacy
Chair of Organic Chemistry I, University of Erlangen-Nürnberg
Henkestrasse 42, 91054 Erlangen (Germany)
Fax: (+49)9131-85-26865
E-mail: tsogoeva@chemie.uni-erlangen.de
Homepage: http://www.chemie.uni-erlangen.de/oc/tsogoeva/
Entry
R
Catalyst
Yield [%]
ee [%][a]
45 (S)[b]
1
2
3
4
5
6
PMP
PMP
PMP
NBz
NBz
NBz
1
2
3
1
2
3
47
29
45
50
40
21
rac
6 (S)[b]
>99 (R)[c]
86 (R)[c]
58 (R)[c]
Dr. T. E. Shubina, Prof. Dr. T. Clark
Computer Chemistry Center, University of Erlangen-Nürnberg
Nägelsbachstrasse 25, 91052 Erlangen (Germany)
[**] We gratefully acknowledge generous financial support from the
Deutsche Forschungsgemeinschaft (SPP 1179 “Organocatalysis”)
and generous amount of computational time from HLRBII (LRZ).
[a] Determined by chiral HPLC analysis and compared with authentic
racemic material. [b] The stereochemistry was established by compar-
ison with literature data.[7] [c] The absolute configuration was established
by X-ray crystallographic analysis.[9] rac=racemic; PMP=para-methoxy-
phenyl; Bz=benzoyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200800849.
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Table 2: Scope of Mannich-type reactions catalyzed by primary amine–
thiourea organocatalyst 1.
The use of chiral amine–thioureas 2 and 3 in the reaction
of acetone with N-benzoylhydrazone gave the products in
86% and 58% ee and in 40% and 21% yields, respectively
(Table 1, entries 5 and 6).
Remarkably, under the same conditions, catalyst 1 showed
excellent enantioselectivity with greater than 99% ee and
50% yield of the isolated product (Table 1, entry 4). It is
noteworthy that the less stable aromatic N-Boc-imines (Boc =
tert-butoxycarbonyl) are possible substrates for this catalytic
reaction.[10]
Impressed by the high enantioselectivity observed with
N-benzoylhydrazone 5, we focused our attention on a detailed
investigation of this reaction catalyzed by amine–thiourea 1.
Additional solvent screening studies demonstrated that
toluene, first chosen, was the optimal solvent under the
reaction conditions used.[9] Hence, Mannich-type reactions of
different ketones with several N-benzoylhydrazones were
performed in toluene with catalyst 1 (Table 2).
When aliphatic ketones were reacted with the N-benzoyl-
hydrazone, moderate to good yields (Table 2, entries 1–6)
were obtained. Cyclic ketones underwent reaction with
a-hydrazonoesters to give higher yields (Table 2, entries 7–
11). The enantioselectivities obtained were excellent for
essentially all the ketones explored, including the branched or
sterically hindered ones, which gave ee values of up to more
than 99% (Table 2).
Entry
Product
Yield [%][a]
50
ee [%][b,c]
de [%][b]
1
2
>99
>99
–
–
86
1.4:1 rr
(8a/8b)
>99 (syn)
>99 (anti)
40 (anti)
90 (syn)
99 (anti)
3
4
82
72 (anti)
80
>99
–
13:1 rr
(10a/10b)
>99 (syn)
>99 (anti)
29 (anti)
The use of unsymmetrical ketones, such as methylethyl
ketone and methylpropyl ketone, introduced the problem of
regioselectivity (Table 2, entries 2 and 4). Addition of methyl-
propyl ketone provided products 10a and 10b with good
regioselectivity (13:1) and excellent enantioselectivity,
whereas methylethyl ketone afforded products 8a and 8b
with modest regioselectivity (1.4:1) and high enantioselectiv-
ities (greater than 99% ee, Table 2, entries 2 and 4).
Interestingly, whereas acyclic ketones gave anti-Mannich
products, an excess of syn diastereomers was observed with
the cyclic ketones (Table 2, entries 2–4 versus entries 7–11).
The syn and anti diastereomeric products were generated
with high ee values (82–99%), but with low to moderate
diastereoselectivities (8–72%; Table 2, entries 2–4 and 7–11).
The effect of the N-benzoyl group on the reaction was
additionally examined in the reaction of para-substituted
N-benzoylhydrazones with cyclohexanone. Intriguingly, elec-
tron-withdrawing groups on the benzoyl moiety led to an
increase of the reaction rate (6–7 h reaction time compared to
17 h; see Table 2, entries 8 versus 9 and 10). On the other
hand, electron-donating groups decrease the rate (44 h
reaction time; see Table 2, entry 8 versus 11).
5
6
54
45
>99
–
–
97
>92 (syn)
>82 (anti)
7
88
19 (syn)
>96 (syn)
>94 (anti)
8
87
89
85
83
45
8 (syn)
8 (syn)
8 (syn)
9 (syn)
–
>94 (syn)
>92 (anti)
9
>95 (syn)
>90 (anti)
10
11
12
>93 (syn)
>92 (anti)
Whereas the present Mannich-type reaction is simple in
execution and uses readily available reagents, the elucidation
of its mechanism is appealing.
Until now, most researchers have proposed[11] the involve-
ment of the enamine mechanism in amine-catalyzed reactions
that involve carbonyl group activation. In 1974, Hajos and
Parrish postulated a combined carbinolamine and enol
mechanism in the Robinson annulation.[12a] Nine years earlier,
Spencer et al. appear to have ruled out the possibility of the
enol mechanism on the basis of Bredtꢀs rule for this
>99
[a] Yields of isolated products. [b] Determined by chiral phase HPLC
analysis. [c] The absolute configurations at the stereocenters were
established by X-ray crystallography of the products, anti-15 and 18.[9]
rr=regioisomer ratio.
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Communications
cyclization reaction, and instead favored the enamine mech-
anism.[12b]
More recently, Clemente and Houk presented computa-
vent effects). The smallest energy difference, 5.9 kcalmolÀ1,
between the two adducts was obtained at the MP2/6-311 +
G*//B3PW91/6-31G* level of calculations (gas phase calcu-
lation, see Scheme S1 of the Supporting Information).
It appears that the primary amine–thiourea catalyst
expands the mechanistic paradigm to include enol-based
chemistry together with the now-traditional enamine amino-
catalysis, wherein the amine–thiourea may serve to stabilize
the enol tautomer of the ketone through hydrogen bonding
(see Scheme S1 of the Supporting Information). This sugges-
tion is consistent with the emerging body of evidence by
Jacobsen and co-workers that thioureas are particularly adept
in anion binding.[17]
tional evidence that supported the enamine mechanism,
partly because the transition state that leads to a carbinol-
amine intermediate could not be located.[13] In 2004 List et al.
repeated Hajosꢀ experiment and observed greater than 90%
18O incorporation by using 18O-enriched water.[14] They
deduced that this resulted from the hydrolysis of an enamine
intermediate in the reaction but observed only oxazalidinone
intermediates in their proton NMR study. In contrast, Hajos
and Parrish observed only 7.2% 18O incorporation.[12a,15]
Another 18O-marker study of a primary amine catalyzed
decarboxylation of b-keto acids by Lerner and Barbas proved
that imine and enamine intermediates are formed in this type
of reaction.[16]
These early results encouraged us to study the primary
amine–thiourea (1) catalyzed addition reaction of acetone to
5 (under Argon) in the presence of a large excess (15 equiv) of
18O-enriched water (97% 18O, Aldrich).[9] Product 7 proved to
be unstable to GC-MS analysis, therefore ESI-MS methods
were used to study this reaction.
Given the wealth of possible conformations between enol/
enamine and a-hydrazonoester 5, a number of transition-state
(TS) structures and the corresponding initial complexes were
identified (Figure 2, only representative TS structures are
shown).
Whereas the peak at m/z 303 pertains to the incorporation
of 18O into product 7b during hydrolysis, indicating enamine
mechanism, the peak at m/z 301 corresponds to 16O-contain-
ing product 7a with 16O from the ketone, which might be
formed by the enol mechanism. From these ESI-MS experi-
ments (Scheme 1 and the Supporting Information) we
concluded that both the enol and enamine mechanisms
might indeed be involved in our primary amine–thiourea
catalyzed Mannich-type reaction.
Figure 2. Transition-state structures located for the enamine (TS1,
R product) and enol (TS2, S product; TS3, R product) mechanisms,
respectively. Computed at the B3PW91/6-31G* (top number) and
MP2/6-31G*//B3PW91/6-31G* (bottom number) levels of theory.
Numbers within structures indicate hydrogen bond lengths.
Scheme 1. 18O-incorporation experiment studied by ESI-MS methods.[9]
Hence, we studied the reaction of 1 with acetone
computationally, considering the possibilities of both the
enamine and enol mechanisms. Preoptimization of the
transition-state structures for the formation of the R and
S products by both the enol and enamine mechanisms were
carried out at the semiempirical AM1 level. The results
indicated, to our surprise, a preference for the enol over the
enamine mechanism. Seeking to verify these early indications,
we then employed more accurate density functional theory
calculations in conjunction with single point energy minimi-
zations at the MP2 level.[9]
Indeed, the complexation of the enol form of the ketone
with catalyst 1 is preferred over the formation of the enamine
at all computational levels employed, including a self-
consistent reaction field (SCRF) solvation calculation.[9] The
solvation effect is small and the enol adduct was confirmed to
be preferred over the enamine by 9 kcalmolÀ1 at the
B3PW91/6-31G* level (9.2 kcalmolÀ1 with inclusion of sol-
The rate-determining step for the formation of product is
the addition of the enamine or enol to the imine, respectively.
For the enamine mechanism, formation of the transition state
leading to the R product (TS1 R in Figure 2; TS4 R, TS5 R—
see Figure S1 of the Supporting Information) is less unfavor-
able (DE + ZPE ꢀ 16–20 kcalmolÀ1, B3PW91/6-31G*); prob-
ably because of the absence of steric and repulsive inter-
actions and the additional stabilization from the formation of
hydrogen bonds. Despite many attempts, we were unable to
locate any transition state that led to the S product by the
enamine pathway. The strong intermolecular repulsive inter-
actions between the two bulky phenyl rings of catalyst 1 and
a-hydrazonoester 5, and the reduced conformational flexi-
bility in the hypothetical (AM1 calculated) transition-state
structure leading to the S product suggest the formation of the
transition state leading to the R product is more favorable.
According to the computational results, the transition state
that leads to the S product by the enol pathway is the lowest in
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Chemie
energy among the three most favorable transition states
(TS1–TS3) considered for the two mechanisms (Figure 3).
Solvent effects even appear to underpin this trend (see
Figure 3). The transition states for the formation of both the S
Scheme 3. Alternative reaction mechanism involving an enol inter-
mediate.
in analogy to the recent work of Jacobsen and co-workers on
the cyanosilylation of a ketone assisted by a tertiary amine-
thiourea catalyst.[17] However, they found computationally,
that the pathway by thiourea-bound cyanide is less favorable
with respect to the pathway involving a thiourea-bound
ketone.[17]
In conclusion, for the first time a chiral primary amine–
thiourea organocatalyst has been applied successfully to an
asymmetric Mannich-type reaction of unmodified ketones
with readily available and stable a-hydrazonoesters. The
reaction does not require preformed enolate equivalents and
provides corresponding products 7–18 in good to high yields
(up to 89%) and excellent enantioselectivities (up to
> 99% ee). Moreover, we present the first piece of evidence
for an enol mechanism in a primary amine–thiourea catalyzed
Figure 3. Reaction energy profiles for the reaction going through the
enamine and enol mechanisms, DE+ZPE in kcalmolÀ1, at the
B3PW91/6-31G* (topentry), MP2/6-31G*//B3PW91/6-31G* (middle
entry), and B3PW91/6-31G* SCRF (bottom entry) level of theory. The
energy profiles for the two mechanisms are compared relative to each
other. Init=initial.
and R products by the enol pathway (TS2 S and TS3 R,
Figure 2; TS6 S, TS7 R, and TS8 R—see Figure S1 of the
Supporting Information) pertain to activation barriers of 11.7
and 20.3 kcalmolÀ1 (B3PW91/6-31G*), respectively (11.7 and
17.8 kcalmolÀ1 at MP2/6-31G*//B3PW91/6-31G*).
À
C C bond-forming transformation—the Mannich-type reac-
tion. The use of the easily accessible bifunctional primary
amine–thiourea catalysts in other valuable organic trans-
formations, as well as additional mechanistic studies are
ongoing in our laboratory.
However, the formation of the final R product–catalyst
complex (1·R)enol is more favorable thermodynamically than
the formation of the S product–catalyst complex (1·S)enol by
3.8 kcalmolÀ1 (B3PW91/6-31G*); 6.3 kcalmolÀ1 at MP2/6-
31G*//B3PW91/6-31G*}. The level of energy of the corre-
sponding final complex (1·R)enamine as shown in Figure 3
differs from that of (1·R)enol only because of a different
hydrogen-bonding pattern. Thus, the calculations suggest
that, whereas the formation of the S product by the enol
pathway is favored kinetically, the overall reaction might be
thermodynamically controlled (i.e. initially faster formed
(1·S)enol could have been transformed gradually into more
stable (1·R)enol).
To validate this computational finding we have stirred
racemic Mannich product 18 in the presence of 15 mol% of
amine–thiourea 1 (Scheme 2). The enantiomeric excess was
determined after 3, 5, 7, and 10 days, respectively. Succes-
sively larger enrichment of R product was observed (5.8% ee,
9.7% ee, 15.7% ee, 25.9% ee after 3, 5, 7, and 10 days,
respectively), confirming the presence of thermodynamic
control.[9]
Received: February 21, 2008
Revised: May 6, 2008
Published online: July 22, 2008
Keywords: asymmetriccatalysis·densityfunctionalcalculations·
.
Mannich-type reactions · thioureas · transition states
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