Synthesis and characterization of binary-complex models of ureas and 1,3-dicarbonyl compounds: Deeper insights into reaction mechanisms using snap-shot structural analysis

Article abstract of DOI:10.1021/jo4028775

The mechanism of the enantioselective Mannich reaction catalyzed by a hydrogen-bond (HB)-donor bifunctional organocatalyst has been fully investigated using experimental evidence and computational analysis. Several binary complexes have been designed as models of a catalyst and a nucleophile, where the urea moieties were linked to a 1,3-dicarbonyl compound through the diphenylacetylene motif. X-ray analysis of models 9 and 10 showed that the two N-H protons of the ureas interacted with the same carbonyl group via a double HB interaction. Further investigation of the crystallographic structure of 11 allowed for the direct observation of the labile ammonium-enolate intermediate formed between a bifunctional amino urea and 1,3-diketone. The β-keto ester-amino urea complex 12 reacted with several electrophiles at a remarkably fast rate to provide the corresponding adducts 15 and 17 as single diastereomers in excellent yields, respectively. A density functional theory calculation disclosed the details of the deprotonation and C-C bond-forming steps of the enantioselective Mannich reaction. The deprotonation of the 1,3-dicarbonyl moiety occurred predominantly via the enol form to give the ammonium - enolate intermediate. These results should provide a deeper and more accurate understanding of the functional roles of the HB-donor and Bronsted base moieties of the catalyst.

Full text of DOI:10.1021/jo4028775

Article
pubs.acs.org/joc
Synthesis and Characterization of Binary-Complex Models of Ureas
and 1,3-Dicarbonyl Compounds: Deeper Insights into Reaction
Mechanisms Using Snap-Shot Structural Analysis
Takumi Azuma,† Yusuke Kobayashi,† Ken Sakata,‡ Takahiro Sasamori,§ Norihiro Tokitoh,§
and Yoshiji Takemoto*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
§Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
S
* Supporting Information
ABSTRACT: The mechanism of the enantioselective Man-
nich reaction catalyzed by a hydrogen-bond (HB)-donor
bifunctional organocatalyst has been fully investigated using
experimental evidence and computational analysis. Several
binary complexes have been designed as models of a catalyst
and a nucleophile, where the urea moieties were linked to a
1,3-dicarbonyl compound through the diphenylacetylene
motif. X-ray analysis of models 9 and 10 showed that the two N−H protons of the ureas interacted with the same carbonyl
group via a double HB interaction. Further investigation of the crystallographic structure of 11 allowed for the direct observation
of the labile ammonium−enolate intermediate formed between a bifunctional amino urea and 1,3-diketone. The β-keto ester−
amino urea complex 12 reacted with several electrophiles at a remarkably fast rate to provide the corresponding adducts 15 and
17 as single diastereomers in excellent yields, respectively. A density functional theory calculation disclosed the details of the
deprotonation and C−C bond-forming steps of the enantioselective Mannich reaction. The deprotonation of the 1,3-dicarbonyl
moiety occurred predominantly via the enol form to give the ammonium−-enolate intermediate. These results should provide a
deeper and more accurate understanding of the functional roles of the HB-donor and Brønsted base moieties of the catalyst.
tertiary amine and HB-donor moieties of these catalysts has
been proposed to account for the significant enhancement in
the rate and stereoselectivity of these reactions (ternary
complex A in Figure 1).5a
INTRODUCTION
■
Enzymes often use interdigitated hydrogen-bonding networks
to promote specific reactions under mild conditions.1 During
the past decade, a growing number of organocatalytic systems
have been developed by chemists as artificial small molecule
systems that are capable of mimicking enzymes,1d and these
systems have attracted considerable interest from synthetic
organic chemists because of their ease-of-handling, low level of
toxicity, and low cost.2 The mechanisms of many different
organocatalyzed reactions have also been explored using
computational analyses3 because a thorough understanding of
these reaction mechanisms could lead to improvements in their
catalytic activities as well as help to provide a deeper
understanding of enzyme-catalyzed biological phenomena.
Urea and thiourea catalysts are representative of a group of
organocatalysts that activate Lewis basic substrates through the
formation of two hydrogen bonds.4 In 2003, we reported that
bifunctional thiourea catalysts5 bearing H-bond donors and
Lewis base functionalities promoted the Michael addition of
1,3-dicarbonyl compounds to nitroalkenes to give the Michael
adducts in good yields and high enantioselectivities.5a
Following from this work, an increasing number of asymmetric
reactions catalyzed by a variety of HB-donor bifunctional
organocatalysts have been developed.6,7 The cooperative
activation of the nucleophile and the electrophile by the
Several theoretical studies were subsequently conducted on
the bifunctionality of chiral thiourea-based organocatalysts,8
which resulted in a slightly different mode of activation being
proposed. According to this proposal, the nucleophile was
sequentially activated by the thiourea and the tertiary amine,
with the electrophile being activated by the resulting
ammonium proton8d (ternary complex B in Figure 1).
Although this new mechanism, which was based on a DFT
calculation, was more promising than the original one, none of
the proposed intermediates have been identified experimen-
tally. For this reason, the details of this reaction mechanism
remain unknown, even though a better understanding of this
mechanism could be critical for the development of improved
innovative catalytic asymmetric reactions. In sharp contrast to
primary and secondary amine organocatalysts, which activate
substrates via the formation of covalent bonds,9 the
intermediates formed during thiourea-catalyzed reactions
cannot be detected spectroscopically because of the small
Received: January 7, 2014
Published: January 22, 2014
© 2014 American Chemical Society
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this study, we describe the synthesis of four binary complex
models 9−12 (Scheme 1) bearing the β-turn motif and the
Scheme 1. Synthesis of the Binary-Complex Models
Figure 1. Proposed mechanism of the bifunctional thiourea-catalyzed
reaction.
association constants resulting from the formation of binary
complexes between the catalyst and the substrate (complex C
in Figure 2). It would therefore be difficult to verify the
subsequent determination of their three-dimensional structures
by 1H NMR and X-ray crystallographic analyses to elucidate the
intramolecular interactions between the thiourea moiety and
1,3-dicarbonyl fragment. Finally, the Mannich reaction between
the N-Boc-imine and binary-complex model 12 was inves-
tigated to identify the absolute configuration and stereo-
selectivity of the products. In addition, DFT calculations were
used to clarify the mechanistic details of the Mannich reaction
and rationalize the experimental results.
Figure 2. Conformationally rigid binary-complex models D with a
diphenylacetylene motif.
existence of the reactive enol and/or enolate intermediates10
predicted by computational analysis. Furthermore, it would not
be possible to clearly establish the roles of individual active sites
in the catalytic processes.
RESULTS AND DISCUSSION
To overcome this inevitable challenge, we planned to
synthesize thermodynamically stable binary complexes that
could mimic the intermediate formed between the catalyst and
nucleophile via ternary complex B and evaluate their structural
by spectroscopic properties. It was envisaged that a properly
constructed motif would enable the direct observation of the
labile reaction species.11 With this in mind, the diphenylace-
tylene unit was selected as an ideal covalent linker for the
thiourea and 1,3-dicarbonyl compounds (complex model D in
Figure 2) because the 2-amino-2′-carboxyldiphenylacetylenes,
which were developed by Kemp, are known to function as β-
turn motifs in artificial β-sheet structures,12 and it was
envisaged that two fragments linked by this unit would form
the appropriate intramolecular hydrogen bonding interactions
between the carbonyl oxygen(s) and the N−H proton(s).13 In
■
Synthesis of the Diphenylacetylene-Linked Ureas and
Aminoureas. We designed four binary-complex models 9−12
(Scheme 1) bearing a diphenylacetylene core that was capable
of forming a β-turn conformation with an intramolecular
Ndonor−Oacceptor hydrogen-bonding interaction. A urea was used
as the hydrogen bond donor group instead of a thiourea
because the high reactivity of thioureas can cause problems
during the synthesis of target molecules.14 Furthermore, to
develop a deeper understanding of the effect of the
bifunctionality of the catalysts, both the N-(2-dimethylamino-
cyclohexyl)urea and N-arylurea were incorporated in the
binary-complex models. In contrast, the 1,3-diketone and β-
keto ester were linked to the other side of the diphenylace-
tylene core as hydrogen bond acceptors. The synthesis of these
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models is shown in Scheme 1. Two different types of the upper
fragment 3 and 4 were prepared from 2-ethynylaniline (2). The
reaction of 2 with arylisocyanate provided the corresponding
urea 3 in high yield. The amino urea 4 was obtained by the
sequential treatment of 2 with triphosgene and N,N-
dimethylcyclohexyl-1,2-diamine. The iodoketones 5 and 7
were acylated under basic conditions for the synthesis of the
lower parts of the hydrogen-bond acceptors, and gave the
corresponding diketone 6 and keto ester 8 products in good
yields, respectively. We then proceeded to investigate the
coupling of the upper and lower parts. The Sonogashira
coupling15 reactions of alkyne 3 with aryl iodides 6 and 8
proceeded smoothly in the presence of Pd(PPh3)2Cl2 and CuI
to afford the desired products 9 and 10 in 83 and 60% yields.
The binary-complex models 11 and 12 of the bifunctional urea
catalyst were synthesized by the coupling reactions of alkyne 4
with the aryl iodides 6 and 8, respectively, in 75 and 85% yields
under the same reaction conditions. Unfortunately, all of our
attempts to prepare the corresponding thiourea adducts using a
variety of different conditions were unsuccessful.
bonded complex 9 existed in both its keto and enol forms 9K
and 9E in a ratio of 45:55, whereas the non-hydrogen-bonded
1,3-diketone 6 existed almost exclusively in its enol form
(1:99). These results indicated that the internal hydrogen bond
between the diketone and the urea was favored to such an
extent that the six-membered hydrogen-bonding interaction of
the 1,3-diketone moiety was dissociated.
To gain deeper insight into the structure of 9, we grew good
quality crystals of 9 for X-ray crystallographic analysis. The
results of the X-ray analysis revealed that the crystals of 9
consisted of the keto form 9K, as shown in Figure 4. We
Structural Analysis of the Binary-Complex Analogues
by NMR and X-ray Crystallography. Having successfully
synthesized four of the desired models, we proceeded to
investigate the 1H NMR of compound 9 to determine whether
this compound would readily form intramolecular hydrogen
1
bonds between its diketone and urea moieties. The H NMR
spectra of 3, a 1:1 mixture of 3 and 6, and binary-complex
model 9 are shown in Figure 3. Although the spectrum of diaryl
Figure 4. X-ray structure of 9K. Selected bond length and angles:
O(2)−H(4) 2.11 Å; O(2)−H(5) 2.14 Å; C(15)−C(16)−C(17) 173°;
C(16)−C(17)−C(18) 172°.
anticipated that each NH proton of the urea would form an
independent hydrogen bond with each carbonyl oxygen atom
of the diketone (complex model D in Figure 2). Surprisingly,
however, both NH protons of the urea only interacted with the
proximal carbonyl oxygen of the diketone via a bifurcated
hydrogen bond (NH···O = 2.14 and 2.11 Å), and the remaining
carbonyl group was situated orthogonal to the hydrogen-
bonded ketone and did not interact with any of the other
functionalities. The bond angles of the two sp carbons were 172
and 173°, indicating that the linker between the two aryl groups
had bent slightly to maintain the required thermodynamically
stable conformation. This experimental observation implied
that the alkyne moiety was flexible enough to preserve a
favorable interaction17 and confirmed that these models were
suitable for further investigation.
Although the enol form 9E predominated slightly over the
keto form 9K in a CDCl3 solution, our efforts to prepare good-
quality crystals of 9E for X-ray analysis were unsuccessful. We
then turned our attention toward using DFT calculations for 9E
and 9K with B3LYP/6-31G* to identify the thermodynamically
stable three-dimensional structures of these compounds as well
as their most stable forms. The X-ray crystallographic structure
of 9K was directly used as the initial structure for the DFT
calculation of 9K. In contrast, the virtual structure of 9E was
constructed on the basis of the structure of 9K and optimized
using B3LYP/6-31G*. As a result, the keto form 9K was
predicted to be 0.8 kcal/mol less stable than the enol form 9E.
1
Figure 3. Partial H NMR spectra (20 mM in CDCl3) of (a) 3, (b) a
1:1 mixture of 3 and 6, and (c) 9.
urea 3 contained two NH peaks at 7.08 and 7.28 ppm (Figure 3
(a), 20 mM in CDCl3, rt), these NH peaks were shifted slightly
downfield to 7.24 and 7.33 ppm when 3 was mixed with
diketone 6 in a 1:1 ratio (Figure 3 (b)). In contrast, the NMR
spectrum of 9 contained four NH signals, because the diketone
moiety of 9 existed in both its keto and enol forms. Thus, the
NH peaks were at 8.62 and 8.82 ppm in the keto form and
7.80−8.0016 and 8.62 ppm in the enol form (Figure 3 (c)). In
any event, these downfield shifts of the NH signals strongly
suggest that the two NH protons of the urea were hydrogen
bonded to the carbonyl group of the diketone. In addition,
because the chemical shifts of the NH protons of 9 did not
change even under highly dilute conditions (1.25 mM), which
was distinct from the cases of 3, an internal hydrogen bond
would still be formed. It is noteworthy that the hydrogen-
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The most thermodynamically stable structure of 9E is depicted
in Figure 5. The calculated NH···O distances were 2.01 and
Figure 5. Estimated structure of 9E from the DFT calculation.
Figure 7. X-ray structure of 11E. Selected bond length: O(2)−H(19)
2.04 Å; O(3)−H(18) 2.07 Å; O(2)−H(1) 1.74 Å; O(3)−H(1) 2.49 Å.
2.04 Å and, therefore, much shorter than the values observed
for 9k in the solid state. The OH···O distance (internal
hydrogen bond) was 1.72 Å.
introducing the tertiary amine to the catalyst, the acidic proton
of the 1,3-diketone was completely deprotonated to afford a
thermodynamically stable enolate anion. This rationale
reasonably explains the distinct behavior of the binary-complex
models 9 and 11 in terms of the ratios of the keto and enol
forms. Surprisingly, however, the interaction between the
ammonium proton and the carbonyl oxygen CO(2)
proximal to alkyne was stronger than the interaction with the
distal carbonyl oxygen CO(3). The distances between the
ammonium proton and the carbonyl oxygens O(2) and O(3)
were 1.74 and 2.49 Å.
We then examined the chemical structure of amino urea 11
1
by NMR and X-ray analysis. The H NMR spectra of 4, a 1:1
mixture of 4 and 6, and the binary-complex model 11 are
shown in Figure 6. In a similar manner to 9, the NH protons of
We then proceeded to investigate the cyclic β-keto ester
derivatives 10 and 12 bearing less acidic protons to clarify their
structures and properties compared with those of the acyclic
diketones 9 and 11. The 1H NMR spectra of 3, a 1:1 mixture of
1
3 and 8, and 10 are shown in Figure 8, whereas the H NMR
spectra of 4, a 1:1 mixture of 4 and 8, and 12 are shown in
Figure 9. A comparison of these spectra strongly indicated that
the β-turn mimetics 10 and 12 possessed an internal hydrogen
bond between their urea NH protons and one of the carbonyl
groups of their keto esters. In addition, only the keto form
1
(>99%) was detected in the H NMR spectra of 10 and 12,
1
Figure 6. Partial H NMR spectra (20 mM in CDCl3) of (a) 4, (b) a
1:1 mixture of 4 and 6, and (c) 11.
11 were shifted downfield in comparison to those of 4, which
confirmed the existence of an internal hydrogen bonding
interaction between the urea and the diketone (Figure 6, (a) vs
(c)). The ratio of the keto form 11K to the enol form 11E,
however, did not change in a similar manner to that observed
for compound 6 and retained the same value (11K:11E =
<1:>99). The X-ray structure of 11 clearly demonstrated that
ammonium enolate 11E was generated by the reaction of the
1,3-diketone with the dimethylamino group and that both of
the oxygen atoms (i.e., CO(2) and CO(3)) of the
resulting enolate anion formed double hydrogen bonds with an
ammonium proton and either an N(2)H(18) or N(3)H(19)
proton. The precise positions of the two NH protons and the
ammonium proton were estimated by the DFT calculation on
the basis of the X-ray structure of 11E (Figure 7).18 By
1
Figure 8. Partial H NMR spectra (20 mM in CDCl3) of (a) 3, (b) a
1:1 mixture of 3 and 8, and (c) 10.
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NMR spectra. The detailed reaction mechanism of 12 using
DFT calculation will be discussed below.
Nucleophilic Reactions of Binary-Complex Models 11
and 12 with Several Electrophiles. Having identified the
precise 3D structures of the binary-complex models 11 and 12,
we proceeded to investigate their reactions with several
electrophiles to determine whether these reactions would
proceed in the same way as the corresponding and previously
reported catalytic reactions (Scheme 2).5a,e,h
Scheme 2. Nucleophilic Reactions of the Binary-Complex
Models 11 and 12
1
Figure 9. Partial H NMR spectra (20 mM in CDCl3) of (a) 4, (b) a
1:1 mixture of 4 and 8, and (c) 12.
whereas the non-hydrogen-bonded β-keto ester 8 existed as an
80:20 mixture of its keto and enol forms in solution.
Furthermore, these results were consistent with the trends
1
observed for compounds 6 and 9. The H NMR spectrum of
amino urea 12 contained a pair of signals because of the
existence of two diastereomers resulting from the chirality of
the β-keto ester moiety. Because β-keto ester 12 possessed a
less acidic proton than diketone 11, the equilibrium for the
deprotonation reaction of 12 by the internal amine was biased
toward 12K, and it was therefore not possible to detect the
1
enolate form by H NMR.
We succeeded in growing good-quality crystals of 10, and the
X-ray crystal structure of this urea−keto ester complex is shown
in Figure 10. In a manner similar to that of compound 9, the X-
Disappointingly, the reaction of 11 with β-nitrostyrene gave a
complex mixture due to the instability of the products.
However, the same compound 11 underwent a Mannich
reaction with N-Boc-imine 13 to give the desired product as a
diastereomeric mixture (ca. 6:4), presumably because of the
epimerization of the 1,3-dicarbonyl moiety.5h We then changed
the substrate from diketone 11 to keto ester 12, which would
provide a chiral quaternary carbon center. In contrast to 11, the
Mannich reaction of 12 with N-Boc-imine 13 was complete
within 10 min and proceeded stereoselectively to give the
addition product 15 as a single isomer. The hydrazine
derivative 17 was also synthesized as a single product via the
simple treatment of 12 with di-tert-butyl azodicarboxylate 16 in
CD2Cl2 at room temperature. It should be mentioned that this
reaction proceeded quickly with an unprecedented level of
stereoselectively, demonstrating that amino urea moiety
functioned efficiently to activate the electrophiles and
nucleophiles. The absolute configuration of 17 was determined
by the chemical transformation of 8 into 17 and 20 via a
catalytic asymmetric hydrazination reaction in the presence of
bifunctional catalyst, followed by a Sonogashira coupling
reaction with amino urea 4 (Scheme 3). According to our
previous report, we then performed the aminobenzothiadia-
zine7d (18)-catalyzed reaction of 8 with 16,5e,19 and the desired
adduct 19 was obtained in 97% yield, albeit with 53% ee.20 The
absolute configuration of 19 was elucidated to be S by
Figure 10. X-ray structure of 10. Selected bond length and angles:
O(3)−H(16) 2.17 Å; O(3)−H(17) 2.08 Å; C(12)−C(13)−C(14)
173°; C(13)−C(14) −C(15) 174°.
ray structure of 10 revealed that the two NH protons of the
urea only interacted with the carbonyl oxygen of the ketone via
a bifurcated hydrogen bond. In contrast, the ester group of 10
was oriented perpendicularly to the hydrogen-bonded ketone.
Although we were unable to prepare good quality crystals of 12
for X-ray analysis, we feel it would be reasonable to consider
that the amino urea model 12 would adopt the keto form
1
similar to urea 10 based on the similarities between their H
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Scheme 3. Determination of the Absolute Configuration of
17
Scheme 4. Determination of the Absolute Configuration of
15
comparison with a previous report.5e The subsequent reaction
of 19 with amino urea 4 gave the coupling products 17 and 20
as a mixture of diastereomers (76:24).21 By comparing their 1H
NMR spectrum of this mixture with that of the diastereomeri-
cally pure product 17 derived from 12, the major product
prepared from 19 was revealed to be 17, from which the
absolute configuration of 17 was unambiguously determined to
be S. These experimental results indicated that the aminourea
moieties of 11 and 12 functioned in a similar manner to the
original catalyst, such as 1 and 18. Furthermore, these results
demonstrated that these biaryl compounds were suitable
models for the elucidation of the detailed reaction mechanisms.
Finally, we attempted to determine the absolute config-
uration of 15 in the same manner (Scheme 4), but the
transformation of 8 into 15 was unsuccessful because the retro-
Mannich reaction of 15 proceeded under the Sonogashira
coupling reaction conditions.15 Therefore, we prepared alcohol
21 by the reduction of 15 with NaBH4. The reduction
proceeded diastereoselectively to give the desired monoalcohol
21 as the single isomer. The same alcohol 21 was also
synthesized via an alternative route involving the catalytic
asymmetric Mannich reaction. The asymmetric Mannich
reaction with 8 provided the desired adduct 22 in 89% yield
and 91% ee.22 The absolute configuration of 22 was elucidated
to be (2S,1′R) based on the previous report.5h The reduction of
22 with NaBH4 followed by the coupling reaction of the
resultant adduct 23 with 4 gave the target molecule 21. The
reaction of 23 with 4 gave the coupling product 21 in 84% yield
reaction of 12 with N-methoxycarbonylimine. All of the
theoretical optimizations were performed using Gaussian 0924
at the B3LYP/6-31G* level.25 Once the stationary points were
obtained at the B3LYP/6-31G* level, the harmonic vibrational
frequencies were calculated at the same level to estimate the
Gibbs free energy. All of the Gibbs free energy values reported
in this paper were calculated for a temperature of 298.15 K. All
of the transition structures reported were optimized without
constraints and the intrinsic reaction coordinate (IRC) routes
were calculated in both directions toward the corresponding
minima for each transition-state structure. The IRC calculations
failed to reach the energy minima on the potential energy
surface for some of the transition states and, in those cases, we
therefore carried out geometry optimizations as a continuation
of the IRC path. Since we could not prepare good quality
crystals of 12 for X-ray analysis, the most stable 3D structures
of both the keto and enol forms of 12 were estimated using
DFT calculations. The 1H NMR studies of 12 strongly
suggested that the binary-complex model 12 existed in the
keto forms 12K-1 and 12K-2 (an epimer of 12K-1) in solution,
but the virtual structure of the enol form 12E was also
optimized. The resulting three conformations 12K-1, 12K-2,
and 12E are shown in Figure 11. From the estimated Gibbs free
energies of these three conformers, the enol form 12E and the
keto form 12K-2 were predicted to be 4.1 and 0.9 kcal/mol
above the keto form 12K-1. We then searched for the optimal
structure of N-methoxycarbonylimine and found two con-
formations of the imine (imine A and imine B) (Figure 12).
Imine B was determined to be more stable than imine A by 2.2
kcal/mol. The energy barrier for a conformational change was
3.3 kcal/mol, and the two conformations were therefore in
equilibrium. Next, we searched the transition state TS1 for the
together with a trace amount of 24.23 By comparing their H
1
NMR spectra with that of 21 derived from 12, the major
product prepared from 23 (er = 95.5:4.5) was revealed to be
21, from which the absolute configuration of 15 was
unambiguously determined.
Theoretical Studies on Mannich Reaction of Binary-
Complex Models 12 Based on a Snapshot X-ray
Analysis. The reactions of 12 with several different electro-
philes were revealed to proceed very rapidly and in a highly
stereoselective manner. Furthermore, a detailed 3D structure of
the binary-complex model 11, which would be a hypothetical
reaction intermediate in the corresponding catalytic reactions,
was first clarified by X-ray crystallographic analysis. Based on
these results, we conducted a theoretical study of the Mannich
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Figure 11. Optimized structures of 12. Bond distances characteristic for H-bonds are given in angstroms. Relative Gibbs free energies (kcal/mol) are
in parentheses.
B, Figure 15). In the optimized geometry of the binary complex
IM2a, the ammonium proton only coordinated strongly with
the oxygen atom of the imine with a hydrogen bond distance of
1.79 Å. However, in the optimized geometry of the binary
complex IM2b, the ammonium proton coordinated with both
the oxygen and nitrogen atoms of the imine and the hydrogen
bond distances were longer than that of IM2a. Although imine
A was less stable than imine B, the binary complex IM2a (17.1)
was more stable than IM2b (21.8). We then obtained the
transition state geometries of the two channels (TS2a−3a
,
Figure 12. Optimized structure of the imine.
TS2b−3b) and found that the nature of the hydrogen bond
between the ammonium proton and the imine remained
unchanged mainly from IM2. In both of the transition states,
we observed some weakening of the urea−ketoester interaction
and the strengthening of the ammonium−imine interaction
because of the occurrence of a charge transfer process from the
anionic ketoester to the electron-deficient imine. The optimized
structures of the intermediates following the C−C bond
formation were also obtained. In both channels, the C−C bond
formation reactions were predicted to be kinetically feasible
processes with the transition state TS2a−3a lying 12.0 kcal/mol
above IM2a or TS2b−3b lying 13.1 kcal/mol above IM2b.
However, since TS2a−3a was predicted to be 5.8 kcal/mol lower
in energy than TS2b−3b, it was predicted that the C−C bond
formation in the Mannich reaction would occur predominantly
in channel A. The C−C bond formation was predicted to be
the rate- and stereodetermining step, because this conversion
step from IM2 (17.1) to TS2a−3a (29.1) possessed the highest
energy difference. Although the reaction proceeds via IM3a to
give TM in channel A, there was no intermediate between
TS2b−3b and TM in channel B. The significant stability of TM
(9.8) was attributed to the double intramolecular hydrogen
bonding interaction between MeOCONH and the CO2Me
(2.21 Å) and NMe2 (2.71 Å) groups (Figure 15). Furthermore,
transformation of 12 into an ammonium enolate IM1 like the
binary complex 11 (Figure 13). Although the keto form 12K-1
was energetically more stable than the enol form 12E, the ΔG
(28.0) of TS1K, the transition state from 12K-1 (0.0) into IM1
(8.3), was too large for the internal deprotonation from the
keto ester moiety by the tertiary amine to occur at room
temperature. In contrast, the generation of the enolate IM1
from the enol form 12E via TS1E appeared to be much more
feasible than that from 12K-1, judging from the energy
difference between 12E (4.1) and TS1E (8.1). Taking into
account the good reactivity and high selectivity of the Mannich
reaction of 12, it would be reasonable to consider that the enol
form 12E, which existed only as a trace in solution, must play
an important role in the formation of the ammonium enolate
1
IM1, whereas 12E could not be detected in the H NMR.
Having elucidated the transition-state geometry for the
enolate formation of 12, as shown in Figure 13, we proceeded
to explore the carbon−carbon bond formation reaction and
found two channels for this reaction. According to one channel,
the ammonium proton of IM1 coordinated with imine A
(channel A, Figure 14), whereas in the other channel, the
ammonium proton of IM1 coordinated with imine B (channel
Figure 13. Optimized structures of TS1K, TS1E, and IM1.
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Figure 14. Optimized structures in channel A.
Figure 15. Optimized structures in channel B and TM.
Figure 16. Energy profile of the Mannich reaction.
1
the two NH protons of the urea readily formed hydrogen
bonds with the ketone via double hydrogen bonds in the TM
(2.12 and 2.61 Å). These internal hydrogen bonds significantly
stabilized the final product 18, and effectively provided the
driving force for the Mannich reaction. Furthermore, the energy
profile of the Mannich reaction is shown in Figure 16.26,27
Compared with the transition state affording the other
diastereomer,28 the activation energy for the C−C bond
formation was greater than that of TS2a−2b by 14.1 kcal. This
calculations was consistent with the experimental result where
the Mannich reaction only gave a single isomer 15.
alkynes by H NMR and X-ray crystallography. The properly
constituted models allowed for the direct observation of the
labile and reactive intermediate, which would have been
otherwise very difficult to detect. In the keto-forms of the
binary complex models 9K and 10, only the ketone carbonyl
oxygen proximal to the tether participated in the formation of
intramolecular hydrogen bonding interaction with the two NH
protons of the urea, leading to the formation of a bifurcated
hydrogen bond. In contrast, the diketone complex 11 bearing
an amine−urea moiety, formed an ammonium−enolate
complex and existed in an ion pair, where a double-
hydrogen-bonding interaction between each oxygen atom of
the enolate and each NH proton of the urea was observed. We
also confirmed that this ion pair of the binary complex model
played a crucial role in the efficient and stereoselective reactions
CONCLUSION
■
We have synthesized and presented the detailed structures of
several urea−dicarbonyl complex models linked with diaryl
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(FAB) 373 (MH+, 100); HRMS (ESI) calcd for C17H11F6N2O (MH+)
373.0770, found 373.0767.
of this species with several electrophiles, in a manner very
similar to that of the nonlinked bifunctional amino−(thio)urea
catalysts.4,5
1-[(1R,2R)-2-(Dimethylamino)cyclohexyl]-3-(2-ethynylphenyl)-
urea (4). To a solution of triphosgen (2.2 mmol, 630 mg) in THF (10
mL) was added a solution of 2 (4.3 mmol, 500 mg) and NEt3 (17
mmol, 1.72 g) in THF (10 mL) dropwise at 0 °C. After being stirred
at room temperature for 1 h, the mixture was filtrated through a pad of
Celite, and the filtrate was concentrated in vacuo to give the crude
isocyanate, which was then dissolved in THF (10 mL). To this
solution was added (1R,2R)-N1,N1-dimethylcyclohexane-1,2-diamine
(505 mg, 3.6 mmol), and the resulting mixture was stirred at room
temperature for 5 h. The mixture was then concentrated in vacuo to
afford a crude product, which was purified by silica gel chromatog-
raphy (CHCl3/MeOH = 10:1) to give 4 (981 mg, 80%): white solid;
mp 137−138 °C; [α]25D −17.8 (c 2.30, CHCl3); 1H NMR (CDCl3) δ
8.18 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.29 (br, 1H), 7.29
(dd, J = 7.7, 7.7 Hz, 1H), 6.90 (dd, J = 7.7, 7.7 Hz, 1H), 6.09 (br, 1H),
3.51 (s, 1H) 3.50 (m, 1H), 2.46 (m, 2H), 2.32 (s, 6H), 1.83−1.90 (m,
2H), 1.69−1.70 (m, 1H), 1.15−1.36 (m, 4H) ppm; 13C NMR
(CHCl3) δ 155.3, 141.2, 132.2, 130.1, 121.4, 118.4, 109.7, 83.8, 79.9,
66.3, 52.0, 39.9, 33.3, 25.3, 24.6, 21.1 ppm; IR (ATR) 3304, 2930,
1649 cm−1; MS (FAB) 286 (MH+, 100); HRMS (ESI) calcd for
C17H24N3O (MH+) 286.1914, found 286.1908.
Based on the information obtained from our established
binary-complex models, we conducted a computational
investigation of the stereoselective Mannich reaction, and the
main conclusions of the study can be summarized as follows:
(i) the deprotonation of the methine proton of the 1,3-
dicarbonyl moiety occurred predominantly via the enol form,
even though almost all of the 1,3-dicarbonyl moiety existed in
the keto form in solution; (ii) in the C−C bond-forming step,
the conformation of the imine changed (from imine B to imine
A) to afford a favorable transition state, where only the
carbonyl oxygen atom of the imine interacted rigidly with the
ammonium proton; and (iii) the ammonium enolate
approached the imine exclusively from its Re face28 to give
the corresponding adduct as a single diastereomer.
These results strongly support the reaction mechanism via
the ternary complex B (Figure 1) proposed by Pap
́
ai.8d As
described in this paper, snapshot structural analysis using the
appropriate reaction intermediate has been demonstrated as a
powerful method to accurately elucidate the reaction
mechanism. The application of this snapshot analysis of the
other routes (ternary complex A, Figure 1) is currently
underway29 in our laboratory and will be reported in due
course.
1-(2-Iodophenyl)-3-phenylpropane-1,3-dione (6). To a solution of
LHMDS (15.2 mmol, 15.2 mL, 1.0 M solution in THF) in THF (20
mL) was added 2′-iodoacetophenone (5) (6.09 mmol, 1.50 g) at −78
°C, and the resulting mixture was stirred at −78 °C for 15 min.
Benzoyl chloride (6.71 mmol. 780 μL) was then added to the mixture,
and the resulting solution was stirred at room temperature for 2 h. The
mixture was then quenched with saturated aqueous NH4Cl solution,
and the aqueous layer was extracted three times with AcOEt. The
combined organic layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo to give the crude product as a residue,
which was purified by silica gel chromatography (n-hexane/AcOEt =
EXPERIMENTAL SECTION
■
General Information. All nonaqueous reactions were carried out
under a positive atmosphere of argon in dried glassware unless
otherwise noted. All the solvents and materials were obtained from
commercial suppliers and used without further purification. Column
chromatography was performed on silica gel (230−400 mesh) or silica
gel (NH, 100−200 mesh), and flash column chromatography was
performed on silica gel (spherical/40−100 μm). Reactions and
chromatography fractions were analyzed using precoated silica gel
plate. All melting points were measured on a melting point apparatus
and are uncorrected. IR spectra were measured on FTIR. Unless
1
12:1) to afford 6 (1.53 g, 72%): pale yellow oil; H NMR (CDCl3) δ
7.95−7.98 (m, 3H), 7.52−7.57 (m, 5H), 7.12−7.16 (t, J = 7.7 Hz,
1H), 6.57 (s, 1H) ppm (enol OH proton could not be observed); 13C
NMR (CDCl3) δ 190.7, 183.7, 142.2, 140.5, 134.6, 132.7, 132.6, 129.2,
128.7, 128.2, 127.2, 97.8, 93.0 ppm; IR (ATR) 3046, 1595 cm−1; MS
(FAB) 351 (MH+, 100); HRMS (ESI) calcd for C15H12IO2 (MH+)
350.9877, found 350.9872.
Methyl 8-Iodo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxy-
late (8). To a solution of NaH (19.2 mmol, 460 mg, 60% dispersion
in mineral oil) in dimethyl carbonate (20 mL) was added a solution of
731 (4.3 mmol, 500 mg) in dimethyl carbonate (10 mL) at room
temperature. After being stirred at 70 °C for 2 h, the mixture was
quenched with saturated aqueous NH4Cl solution. The aqueous layer
was extracted three times with AcOEt. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel chromatography (NH, n-
hexane/AcOEt = 20:1) to afford 8 (1.21 g, 72%): pale yellow
1
otherwise noted, NMR spectra were obtained in CDCl3. H NMR
(500 MHz) spectra were measured and chemical shifts are reported in
δ (ppm) relative to TMS (in CDCl3), which was used as an internal
reference standard. 13C NMR (126 MHz) spectra were also recorded
1
and referenced to the residual CHCl3 signal. H NMR multiplicities
are reported as follows: br = broad; m = multiplet; s = singlet; d =
doublet; t = triplet; q = quartet; sep = septet. Low-resolution and high-
resolution mass spectra were obtained using an LCMS-IT-TOF fitted
with an ESI or FAB. Optical rotations were recorded on a polarimeter
with a path length of 1 cm; concentrations are quoted in grams per
100 mL. [α]D values were measured in 10−1 deg cm2 g−1. Enantiomeric
excesses were determined by high-performance liquid chromatography
(HPLC) analysis. Unless otherwise noted, all materials and solvents
were purchased and used without purification. All noncommercially
available substrates were prepared according to the literature
procedure as indicated below.
1
amorphous; H NMR (CDCl3)* major isomer δ 7.98 (d, J = 7.8 Hz,
1H), 7.24 (d, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.8, 7.8 Hz, 1H), 3.78 (s,
3H) 3.68 (dd, J = 10.0, 4.9 Hz, 1H), 2.97−3.15 (m, 2H), 2.30−2.50
(m, 2H) ppm; minor isomer δ 7.92 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8
Hz, 1H), 6.91 (dd, J = 7.8, 7.8 Hz, 1H), 3.84 (s, 3H), 2.70 −2.74 (m,
2H), 2.42−2.51 (m, 2H) ppm (one peak of enol OH proton could not
be observed); 13C NMR (126 MHz, CDCl3) δ 191.9, 173.1, 170.3,
164.7, 145.7, 143.2, 141.7, 141.5, 133.5, 131.9, 131.8, 130.9, 129.2,
127.6, 93.5, 90.5, 54.5, 52.5, 51.9, 29.4, 28.7, 25.5, 20.2 ppm (one peak
of minor isomer could not be observed due to overlapping); IR (ATR)
2949, 1739, 1687 cm−1; MS (FAB) 331 (MH+, 100); HRMS (FAB)
calcd for C12H12IO3 (MH+) 330.9831, found 330.9825. *Mixture of
keto form (major) and enol form (minor).
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-[[2-(3-oxo-3-
phenylpropanoyl)phenyl]ethynyl]phenyl]urea (9). To a solution of 3
(0.54 mmol, 201 mg) and 6 (0.59 mmol, 207 mg) in THF/i-Pr2NH
(10 mL, 1: 1) were added Pd(PPh3)2Cl2 (5 mol %, 19 mg) and CuI
(10 mol %, 10 mg) successively at room temperature. After being
stirred at room temperature for 1 h, the mixture was quenched with
1-[3,5-Bis(trifluoromethyl)phenyl]-3-(2-ethynylphenyl)urea (3).
To a solution of 230 (2.0 mmol, 234 mg) in THF (5.0 mL) was
added 3,5-bis(trifluoromethyl)phenyl isocyanate (2.0 mmol, 510 mg).
After being stirred at room temperature for 6 h, the mixture was
concentrated in vacuo. The residue was purified by recrystallization (n-
hexane/AcOEt) to afford 3 (707 mg, 95%): white solid; mp 197−198
1
°C; H NMR (acetone-d6) δ 9.45 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H),
8.18 (s, 2H), 8.05 (s, 1H), 7.63 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.40
(dd, J = 7.8, 7.8 Hz, 1H), 7.06 (dd, J = 7.8, 7.8 Hz, 1H), 4.13 (s, 1H)
ppm; 13C NMR (acetone-d6) δ 152.7, 142.7, 141.4, 133.3, 132.51 (q,
JC−F = 33 Hz), 124.4 (q, JC−F = 275 Hz), 130.7, 123.4, 120.2, 119.1,
115.9, 111.9, 86.4, 79.8 ppm; IR (ATR) 3313, 1657, 1555 cm−1; MS
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saturated aqueous NH4Cl solution. The aqueous layer was extracted
three times with AcOEt, and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel chromatography (n-hexane/AcOEt = 10: 1 →
5:1) to afford 9 (266 mg, 83%): yellow needles; mp 164−165 °C; 1H
NMR (pyridine-d5) δ 8.86 (br, 1H), 8.75 (d, J = 8.3 Hz, 1H), 8.35 (s,
2H), 8.02 (d, J = 8.0 Hz, 2H), 7.99 (br, 1H), 7.70 (s, 1H), 7.63 (d, J =
7.7 Hz, 1H) 7.33−7.55 (m, 8H), 7.04 (dd, J = 7.7 Hz, 1H) ppm (two
peaks could not be observed); 13C NMR (pyridine-d5) δ 186.7, 184.0,
152.3, 141.8, 140.7, 137.2, 133.8, 132.6, 131.9, 131.5, 131.3, 131.0,
130.8, 129.9, 128.9, 128.5, 128.4, 127.0. 126.6, 124.5, 123.2, 123.1,
122.4, 122.3, 122.1, 120.1, 119.0, 118.4, 114.8, 111.2, 96.5, 94.9, 90.2
ppm; IR (ATR) 3332, 2208, 1688, 1661, 1597 cm−1; MS (FAB) 595
(MH+, 45) 105 (100); HRMS (ESI) calcd for C32H21F6N2O3 (MH+)
595.1451, found 595.1453.
Reaction of Binary-Complex Models 11 and 12. General
Procedure. To a solution of 11 or 12 (1.0 equiv) in CD2Cl2
appropriate electrophile was added (1.5 equiv) at room temperature.
After being stirred at room temperature for 10 or 30 min, the mixture
was purified by silica gel chromatography (CHCl3/MeOH). A general
procedure afforded 14 (67%, 100% conversion)*: yellow amorphous
solid; 1H NMR (CDCl3) δ: 8.49 (0.6H, d, J = 8.3 Hz), 8.44 (0.4H, d, J
= 8.6 Hz), 8.04−7.98 (1H, br m), 7.92−7.84 (3H, m), 7.72−7.47 (3H,
m), 7.40−6.83 (11H, m), 6.45−5.92 (2H, m), 5.54−5.58 (0.6H, br
m), 5.51−5.53 (0.4H, br m), 3.78−3.74 (1H, m), 2.77−2.52 (1H, m),
2.25−1.70 (5H, m), 2.35 (3.6H, s), 2.20 (2.4H, s), 1.50−1.10 (4H, m),
1.25 (3.6H, s), 1.22 (5.4 H, s) ppm; HRMS (FAB) calcd for
C44H49N4O5 (MH+) 713.3703, found 713.3712. *Mixture of
diastreomers (60:40).
Methyl 2-[[(tert-Butoxycarbonyl)amino](phenyl)methyl)-8-[[2-[3-
[(1R,2R)-2-(dimethylamino)cyclohexyl]ureido]phenyl]ethynyl]-1-
oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (15). A general
Methyl 8-[[2-[3-[3,5-Bis(trifluoromethyl)phenyl]ureido]phenyl]-
ethynyl]-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (10).
A procedure similar to that described for the preparation of 9 afforded
procedure afforded 15 (77%, 100% conversion): yellow amorphous;
1
1
[α]25 +88.4 (c 1.12, CHCl3); H NMR (CDCl3) δ 8.54 (1H, d, J =
D
10 (152 mg, 60%): yellow prisms; mp 178−179 °C; H NMR (500
8.6 Hz), 8.49 (1H, s), 7.55 (1H, d, J = 7.7 Hz), 7.48 (1H, d, J = 7.7
Hz), 7.46−7.44 (1H, m), 7.38 (2H, d, J = 7.4 Hz), 7.32−7.24 (5H, m),
6.92 (1H, td, J = 7.5, 1.1 Hz), 6.54 (1H, br s), 6.07 (1H, br s), 5.54
(1H, br s), 3.86−3.84 (1H, br m), 3.72 (3H, s), 3.25−3.00 (3H, m),
2.76−2.70 (1H, m), 2.32 (6H, s), 2.26−2.24 (2H, m), 2.00−1.65 (3H,
m), 1.40−1.25 (4H, m), 1.25 (9H, s) ppm; 13C NMR (CDCl3) δ
194.2, 170.6, 155.5, 155.2, 143.4, 143.0, 137.8, 133.0, 131.9, 130.3,
130.2, 128.9, 128.5 (×2), 128.3, 127.9, 123.8, 120.7, 118.2, 110.2, 95.7,
91.5, 79.9, 65.0, 63.0, 55.6, 52.8, 51.5, 40.3, 34.1, 28.1, 27.9, 27.2, 25.8,
25.3 (×2) ppm; IR (ATR) 3393, 3339, 2200, 1733, 1664, 1525 cm−1;
MS (FAB) 693 (MH+, 87), 57 (100); HRMS (FAB) calcd for
C41H49N4O6 (MH+) 693.3652, found 693.3647.
Di-tert-butyl 1-[(S)-8-[[2-[3-[(1R,2R)-2-(Dimethylamino)-
cyclohexyl]ureido]phenyl]ethynyl]-2-(methoxycarbonyl)-1-oxo-
1,2,3,4-tetrahydronaphthalen-2-yl]hydrazine-1,2-dicarboxylate)
(17). A general procedure afforded 17 (96%, 100% conversion): yellow
amorphous; [α]25D +9.4 (c 0.80, CHCl3); 1H NMR (CDCl3, 60 °C) δ
8.63 (1H, s), 8.48 (1H, d, J = 8.0 Hz), 7.48−7.39 (3H, m), 7.32−7.23
(2H, m), 6.89 (1H, t, J = 7.4 Hz), 5.59 (1H, br s), 3.85 (3H, s), 3.84−
3.82 (1H, m), 3.68−3.60 (1H, m), 3.36−3.20 (1H, br m), 3.04−2.98
(1H, m), 2.95−2.91 (1H, m), 2.72−2.66 (1H, m), 2.27−2.23 (1H, m),
2.26 (6H, s), 1.97−1.92 (1H, m), 1.84−1.80 (1H, m), 1.73−1.68 (1H,
m), 1.44 (9H, s), 1.42−1.15 (4H, m), 1.14 (9H, s) ppm (one peak of
NH proton could not be observed); 13C NMR (CDCl3, 60 °C) δ
190.7, 170.3, 155.3, 154.8, 147.2, 142.9, 133.0, 132.4, 131.4, 130.2,
130.1, 128.5, 124.2, 120.7, 118.6, 110.6, 95.6, 91.8, 82.6, 80.6, 76.6,
64.0, 52.9, 52.2, 39.9, 34.3, 30.3, 28.1, 27.9, 26.2, 25.6, 25.5, 21.8 ppm
(one peak could not be observed); IR (ATR) 3407, 3346, 2933, 1747.
1717, 1671, 1524 cm−1; MS (FAB) 718 (MH+, 100); HRMS (ESI)
calcd for C39H52N5O8 (MH+) 718.3810, found 718.3809.
MHz, CDCl3) δ 9.24 (s, 1H), 8.73 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H),
8.16 (s, 2H), 7.48−7.61 (m, 4H), 7.37 (dd, J = 7.9 Hz, 1H), 7.29 (d, J
= 8.5 Hz, 1H), 7.01 (dd, J = 8.5 Hz, 1H), 3.78 (1H, dd, J = 9.2, 5.2
Hz), 3.64 (3H, s), 3.22−3.20 (1H, m), 3.10−3.04 (1H, m), 2.59−2.56
(1H, m), 2.48−2.43 (1H, m) ppm; 13C NMR δ 194.9, 169.6, 152.4,
145.9, 142.1, 140.8, 133.9, 133.4, 132.3, 132.0, 131.8, 131.7, 131.5,
130.7, 130.5, 128.9, 124.4, 123.7, 122.3, 122.0, 119.2,
118.1,117.5,115.7, 110.7, 96.4, 91.6, 55.1, 52.6, 28.2, 25.8 (one peak
could not be observed) ppm; IR (ATR) 3354, 2361, 1743, 1659, 1574
cm−1; MS (FAB) 575 (MH+, 100); HRMS (FAB) calcd for
C29H21F6N2O4 (MH+) 575.1406, found 575.1402.
1-[(1R,2R)-2-(Dimethylamino)cyclohexyl]-3-[2-[[2-(3-oxo-3-
phenylpropanoyl)phenyl]ethynyl]phenyl]urea (15). A procedure
similar to that described for the preparation of 9 afforded 11 (132
mg, 75%): pale yellow prisms; mp 170−171 °C; [α]25D −23.5 (c 0,08,
CHCl3); 1H NMR (CDCl3) δ 8.20 (s, 1H), 8.13 (br, 1H), 8.02 (d, J =
8.3 Hz, 1H), 7.88 (d, J = 6.9 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.45−
7.31 (m, 6H), 7.28−7.24 (m, 1H) 6.88 (dd, J = 7.5, 7.5 Hz, 1H), 6.31
(br, 1H), 5.01 (br, 1H), 3.78−3.75 (m, 1H), 3.49−3.46 (m, 1H), 2.52
(s, 6H), 2.52−2.46 (m, 1H), 2.05−1.80 (m, 3H), 1.56−1.30 (m, 4H)
ppm (one peak of ammonium proton could not be observed); 13C
NMR (CDCl3) δ 188.5, 184.1, 155.8, 145.4, 142.3, 140.4, 132.6, 132.4,
131.0, 130.6, 129.4, 128.7, 128.1, 127.8, 127.2, 127.0, 120.9, 118.6,
111.2, 96.8, 95.0, 89.2, 65.6, 51.1, 38.9, 33.6, 24.9, 24.5, 22.5 ppm; IR
(ATR) 3265, 2144, 1783, 1686, 1601 cm−1; MS (FAB) 508 (MH+,
45), 136 (100); HRMS (FAB) calcd for C32H34N3O3 (MH+)
508.2595, found 508.2598.
Methyl 8-[[2-[3-[(1R,2R)-2-(Dimethylamino)cyclohexyl]ureido]-
phenyl]ethynyl]-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxy-
late (12). A procedure similar to that described for the preparation of
(S)-Di-tert-butyl 1-[8-Iodo-2-(methoxycarbonyl)-1-oxo-1,2,3,4-
tetrahydronaphthalen-2-yl]hydrazine-1,2-dicarboxylate (19).20 To
a solution of 8 (1.0 equiv) and catalyst (0.1 equiv) in CH2Cl2 was
added 16 (2.0 equiv) at an appropriate temperature. After being stirred
at room temperature for 12 h, the mixture was concentrated in vacuo.
The residue was purified by silica gel chromatography (n-hexane/
1
9 afforded 12 (76 mg, 85%): yellow solid; mp 70−71 °C; H NMR
(CDCl3)* major isomer 8.95 (1H, br s), 8.53 (1H, dd, J = 9.0 Hz),
7.58−7.56 (1H, m), 7.50−7.48 (1H, m), 7.44−7.43 (1H, m), 7.33−
7.31 (1H, m), 7.27−7.24 (1H, m), 6.90−6.89 (1H, m), 6.47 (1H, d, J
= 6.6 Hz), 3.78−3.76 (2H, m), 3.77 (3H, s), 3.14−3.12 (1H, m),
3.04−3.00 (1H, m), 2.61−2.23 (4H, m), 2.30 (6H, s), 1.87−1.80 (2H,
AcOEt = 7:1): white solid; mp 61−62 °C; [α]25 +10.6 (53% ee, c
D
1
0.74, CHCl3); 1H NMR (CDCl3, 60 °C) δ 7.86−7.81 (1H, br m), 7.23
(1H, d, J = 7.4 Hz), 7.01 (1H, t, J = 7.4 Hz), 6.46 (1H, br s), 3.85 (3H,
s), 3.50−3.40 (1H, br m), 3.12−3.05 (1H, br m), 2.98−2.93 (1H, m),
2.66−2.60 (1H, m), 1.44 (9H, s), 1.25 (9H, s) ppm; 13C NMR
(CDCl3, 60 °C) δ 189.7, 170.1, 155.6, 146.1, 140.5, 132.8, 128.8, 93.9,
87.6, 83.0, 81.1, 76,2, 52.7, 30.7, 28.2, 28.0, 27.9, 26.3 ppm; IR (ATR)
3309, 2979, 1721 cm−1; MS (FAB) 561 (MH+, 11), 449 (100); HRMS
(FAB) calcd for C22H30IN2O7 (MH+) 561.1098, found 561.1102;
HPLC [Chiralpak AD, n-hexane/2-propanol = 95/5, 1.0 mL/min, λ =
254 nm, retention times: (major) 15.8 min (minor) 35.2 min].
(S)-Methyl 2-[(R)-[(tert-Butoxycarbonyl)amino](phenyl)methyl]-
8-iodo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (22).22
To a solution of 8 (1.0 equiv) and catalyst (0.1 equiv) in CH2Cl2
was added 13 (1.2 equiv) at an appropriate temperature. After being
stirred at room temperature for 12 h, the mixture was concentrated in
m), 1.79−1.77 (1H, m), 1.27−1.15 (4H, m) ppm; minor isomer H
NMR (CDCl3) δ 8.87 (1H, br s), 8.51 (1H, d, J = 8.9 Hz), 7.58−7.56
(1H, m), 7.50−7.48 (1H, m), 7.44−7.43 (1H, m), 7.33−7.31 (1H, m),
7.27−7.24 (1H, m), 6.90−6.89 (1H, m), 6.31 (1H, d, J = 6.6 Hz),
3.78−3.76 (2H, m), 3.77 (3H, s), 3.14−3.12 (1H, m), 3.04−3.00 (1H,
m), 2.61−2.23 (4H, m), 2.30 (6H, s), 1.87−1.80 (2H, m), 1.79−1.77
(1H, m), 1.27−1.15 (4H, m) ppm; 13C NMR (CDCl3) δ 193.7, 193.1,
170.0, 155.5, 145.4, 144.9, 143.6, 143.5, 133.4, 133.3, 133.1, 132.9,
131.6, 131.5, 130.9, 130.6, 130.5, 130.4, 128.6, 128.5, 124.1, 123.7,
120.4, 120.4, 117.6, 117.5, 109.7, 109.7, 96.0, 95.7, 92.2, 91.9, 66.2,
66.0, 54.9, 54.8, 52.7, 52.6, 51.0, 50 0.8, 46.1, 40.3, 40.3, 34.1, 34.0,
28.0, 27.9, 26.0, 25.9, 25.3, 25.2, 24.9, 23.1, 22.8 ppm; IR (ATR) 3336,
2932, 2361, 1741, 1667, cm−1; MS (FAB) 488 (MH+, 100); HRMS
(FAB) calcd for C29H34N3O4 (MH+) 488.2549, found 488.2550.
*Mixture of diastereomers.
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Article
vacuo. The residue was purified by silica gel chromatography (n-
22.7 ppm; IR (ATR) 3422, 1712, 1687 cm−1; MS (FAB) 538
(MH+,4), 106 (100); HRMS (FAB) calcd for C24H29INO5 (MH+)
538.1090, found 538.1092.
hexane/AcOEt = 5:1): white solid; mp 161−162 °C; [α]25 −0.17
D
1
(77% ee, c 2.50, CHCl3); H NMR (CDCl3) δ 7.91 (1H, d, J = 7.7
(1S,2R)-Methyl 2-[(S)-[(tert-Butoxycarbonyl)amino](phenyl)-
methyl]-8-[[2-[3-[(1R,2R)-2-(dimethylamino)cyclohexyl]ureido]-
phenyl]ethynyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene-2-car-
boxylate (24). A procedure similar to that described for the
preparation of 9 afforded the mixture of 21 and 24. When 23 (er =
95.5:4.5) was used as substrate, only 21 was isolated in 84% yield.
When racemic 23 was used as a substrate, 21 and 24 were isolated in
Hz), 7.43 (2H, d, J = 6.9 Hz), 7.31 (2H, dd, J = 7.4, 7.4 Hz), 7.26 (1H,
t, J = 7.4 Hz), 7.20 (1H, d, J = 7.4 Hz), 7.05 (1H, t, J = 7.7 Hz), 6.33
(1H, br s), 5.21 (1H, d, J = 10.3 Hz), 3.53 (3H, s), 3.16−3.13 (2H,
m), 2.67−2.65 (1H, m), 2.30−2.28 (1H, m), 1.36 (9H, s) ppm; 13C
NMR (CDCl3) δ 195.3, 170.5, 155.0, 143.5, 140.9, 138.4, 133.7, 133.1,
129.0, 128.3, 128.3, 127.8, 99.9, 79.7, 63.0, 57.2, 52.4, 29.2, 28.3, 26.2
ppm; IR (ATR) 3436, 2978, 1698 cm−1; MS (FAB) 536 (MH+,7), 206
(100); HRMS (FAB) calcd for C24H27INO5 (MH+) 536.0934, found
536.0933; HPLC HPLC [Chiralpak AD, n-hexane/2-propanol = 95/5,
1.0 mL/min, λ = 254 nm, retention times: (major) 18.0 min (minor)
45.0 min].
46% and 42% yields, respectively: white solid; mp 154−156 °C; [α]25
D
+130.4 (c 0.32, CHCl3); 1H NMR (CDCl3) δ 8.35 (1H, d, J = 8.6 Hz),
7.45 (1H, d, J = 7.4 Hz), 7.38 (1H, d, J = 7.4 Hz), 7.32−7.16 (8H, m),
7.08 (1H, d, J = 8.0 Hz), 6.97 (1H, t, J = 7.4 Hz), 6.23−6.07 (2H, br
m), 5.60 (1H, s), 5.14 (1H, d, J = 9.2 Hz), 3.44 (3H, s), 3.41−3.36
(1H, m), 2.99−2.96 (1H, m), 2.85−2.78 (1H, m), 2.68−2.09 (10H,
m), 2.02−1.64 (3H, m), 1.40−1.08 (4H, m), 1.25 (9H, s) ppm (one
peak of OH proton could not be observed); 13C NMR (CDCl3) δ
173.6, 156.6, 155.5, 141.4, 137.3, 136.6, 131.5, 129.6, 128.3, 128.2,
127.9, 127.5, 121.3, 118.3, 110.9, 89.3, 80.4, 67.9, 66.0, 51.7, 31.9, 31.6,
29.7, 28.1, 25.9, 24.7, 22.7, 22.3, 21.0, 14.1 ppm (six peaks could not
be observed due to overlapping); IR (ATR) 3348, 2951, 1704 cm−1;
MS (FAB) 695 (MH+, 100); HRMS (ESI) calcd for C41H51N4O6
(MH+) 695.3804, found 695.3810.
Determination of the Absolute Configuration of 15 and 17.
A procedure similar to that described for the preparation of 9 afforded
the mixture of 17 and 20. When 19 (er = 76.5:23.5) was used as a
substrate, the ratio 17/20 in the resulting mixture was 76:24. When
racemic 19 was used as a substrate, the ratio 17/20 in the resulting
mixture was 50:50.
1
Mixture of 17 and 20 (50:50): H NMR (CDCl3, 60 °C) δ 8.65
(0.5H, br s), 8.49 (0.5H, d, J = 8.0 Hz), 8.38 (0.5H, d, J = 8.0 Hz),
8.26 (0.5H, br s), 7.48−7.23 (5.0H, m), 6.89 (1H, t, J = 7.4 Hz), 6.69
(0.5H, br s), 5.81(0.5H, br s), 5.59 (0.5H, br s), 3.87 (1.5H, s), 3.85
(1.5H, s), 3.84−3.82 (1H, m), 3.68−3.20 (2H, br m), 3.04−2.23 (4H,
m), 2.26 (3H, s), 2.24 (3H, s), 1.97−1.68 (3H, m), 1.44 (9H, s),
1.42−1.15 (4H, m), 1.14 (9H, s) ppm (one peak of NH proton of 17
could not be observed).
ASSOCIATED CONTENT
■
S
* Supporting Information
Results of catalyst screening in hydrazination and Mannich
1
reaction of 8, copies of H and 13C NMR spectra for all new
(1R,2S)-Methyl 2-[(R)-[(tert-Butoxycarbonyl)amino](phenyl)-
methyl]-8-[[2-[3-[(1R,2R)-2-(dimethylamino)cyclohexyl]ureido]-
phenyl]ethynyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene-2-car-
boxylate (21). To a solution of 15 (0.1 mmol) in MeOH (2.0 mL)
was added NaBH4 (1.0 mmol) at room temperature. After being
stirred at room temperature for 1 h, the mixture was quenched with
saturated aqueous NH4Cl solution. The aqueous layer was extracted
three times with AcOEt, and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel chromatography (CHCl3/MeOH/NEt3=
50:1:0.1 → 20:1:0.1) to afford 21 (77%): white solid; mp 152−154
°C; [α]25D −85.6 (c 0.67, CHCl3); 1H NMR (CDCl3) δ: 7.90 (1H, d, J
= 8.3 Hz), 7.53 (1H, br s), 7.35−7.11 (9H, m), 7.01 (1H, d, J = 7.5
Hz), 6.93 (1H, d, J = 7.5 Hz), 6.31 (1H, d, J = 9.7 Hz), 5.92−5.90
(1H, br m), 5.41−5.39 (2H, br m), 5.15 (1H, d, J = 9.7 Hz), 3.52−
3.47 (1H, br m), 3.41 (3H, s), 2.80−2.78 (2H, m), 2.38−1.95 (4H,
m), 1.87 (6H, s), 1.78−1.59 (3H, m), 1.26 (9H, s), 1.25−1.00 (4H,
m) ppm; 13C NMR (CDCl3) δ: 173.1, 155.9, 155.7, 141.7, 138.5,
137.7, 136.1, 130.8, 129.9, 129.4, 129.3, 128.2, 128.0, 127.8, 127.5,
123.8, 122.0, 121.0, 112.8, 92.7, 90.4, 79.8, 67.4, 66.3, 59.5, 54.7, 51.8,
51.7, 39.3, 34.3, 28.3, 26.3, 25.1, 24.8, 22.9, 21.1 ppm; IR (ATR) 3358,
2934, 1716 cm−1; MS (FAB) 695 (MH+, 100); HRMS (ESI) calcd for
C41H51N4O6 (MH+) 695.3803, found 695.3812.
compounds, and the computational details, and X-ray crystal
structures analysis data of 9K, 10, and 11E (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: takemoto@pharm.kyoto-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge a Grant-in-Aid for Scientific
Research (Y.T.) on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (Japan) and
the Japan Society for the Promotion of Science (JSPS)
Research Fellowship for Young Scientists (T.A.).
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(19) We used aminobenzothiadiazine 18 as a catalyst instead of
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(20) Several trials were unsuccessful, probably because of the steric
hindrance of the iodine group. The full details are described in the
Supporting Information.
(21) When racemic 19 was used as a substrate, the ratio 17 to 20 in
the resulting mixture was 50:50.
(22) The details of trials aimed at improving the enantioselectivity of
the Mannich reaction are described in the Supporting Infomation.
(23) When racemic 23 was used as a substrate, 21 and 24 were
obtained in 46 and 42% yields, respectively.
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(26) B3LYP level calculations showed that the examined reaction is
endothermic. It has been pointed out that DFT calculations using
B3LYP functional underestimate the reaction energies for conjugate
additions.27 Then, we also carried out M06/6-31G**//B3LYP/6-
31G* level calculations, and the results showed that our qualitative
discussion remains unchanged although the reaction is exothermic. See
the Supporting Information.
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(28) The computational details, including the energy profile, are
described in the Supporting Information.
(29) The binary-complex models described in this paper would
predetermine the preference of the reaction mechanism via the ternary
complex B by the linkage. Therefore, as a model of the ternary
complex A, we also investigated the reactions of the electrophiles 25
and 26 with nucleophiles such as nitromethane. However, no
acceleration was observed in the reaction, and only a trace amount
of adduct was obtained. This preliminary result would also make the
ternary complex B more reliable.
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