Dihydrooxazine N-Oxide Intermediates as Resting States in Organocatalytic Kinetic Resolution of Functionalized Nitroallylic Amines with Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b00493

Kinetic resolution of nitroallylic amines was established using chiral α,α-l-diphenylprolinol silyl ether auxiliary through isolation of the dihydrooxazine N-oxide intermediates. Further hydrolyzing the resting states provided tetrahydropyridines in high chemical yields and high to excellent stereoselectivities (up to >20:1 dr and 98% ee). A detailed mechanistic explanation for stereoselective protonation in the dihydrooxazine was probed computationally. In addition, the probable intermediates in α-halogenation of aldehydes (masked with enamines) were isolated to provide crystallographic evidence.

Full text of DOI:10.1021/acs.orglett.6b00493

Letter
pubs.acs.org/OrgLett
Dihydrooxazine N‑Oxide Intermediates as Resting States in
Organocatalytic Kinetic Resolution of Functionalized Nitroallylic
Amines with Aldehydes
Ramani Gurubrahamam, Yan ming Chen, Wan-Yun Huang, Yu-Te Chan, Hsiang-Kai Chang,
Ming-Kang Tsai,* and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan R.O.C.
S
* Supporting Information
ABSTRACT: Kinetic resolution of nitroallylic amines was established
using chiral α,α-L-diphenylprolinol silyl ether auxiliary through isolation of
the dihydrooxazine N-oxide intermediates. Further hydrolyzing the
resting states provided tetrahydropyridines in high chemical yields and
high to excellent stereoselectivities (up to >20:1 dr and 98% ee). A
detailed mechanistic explanation for stereoselective protonation in the
dihydrooxazine was probed computationally. In addition, the probable intermediates in α-halogenation of aldehydes (masked
with enamines) were isolated to provide crystallographic evidence.
he development of the organocatalytic domino/cascade
functionalized tetrahydropyridines (THP) (Scheme 1). The six-
membered nitrogen heterocycles are of high importance as these
T
reaction1 has proven effective in developing complex
structural skeletons that have multistereogenic centers.2 Among
the various reaction sequences, the reaction of aldehyde with
nitroolefins through enamine catalysis is one of the most well-
studied transformations. The revelation of the mechanism
intermediates and rate-determining step (rds) will provide new
understanding in organocascade reactions. In 2011, Blackmond
and Seebach-Hayashi identified the cyclobutane species as an
essential intermediate in the Michael addition of aldehydes to β-
nitrostyrenes.3 These pioneering studies disclosed that the
addition of aldehyde to nitrostyrenes is not as simple as the
original mechanism proposed, rather it proceeds through a
Scheme 1. KR of Nitroallylic Amines with Aldehydes
complex mechanism.4 Seebach, Pihko, Pap
́
ai and their co-
are ubiquitous in numerous natural products and biologically
active pharmaceutical skeletons.10 Considering this, various
organocatalytic methods have been developed for synthesizing
enantioenriched six-membered nitrogen heterocycles under
enamine/iminium and/or hydrogen bonding catalysis.11
workers later noticed a six-membered dihydrooxazine N-oxide
intermediate species in the Michael addition of aldehydes to α,β-
disubstituted nitroolefins.5 Mechanistically, one of the note-
worthy features of this Michael reaction is the virtual role of the
acid additive in protonating either the cyclobutane or oxazine N-
oxide species, which is the rate-determining step.3,5 The intrinsic
information in these mechanisms attracted several groups to
further study the prominent α,α-L-diphenylprolinol silyl ether
catalyst 16 and other organocatalysts with multiple hydrogen
bond donors.7 Herein, we present an interesting kinetic
resolution (KR) of racemic nitroallylic amines 3 by aldehydes
through the isolation of dihydrooxazine N-oxide intermediates 4
as resting states in the Michael reaction. Computational studies
were used to determine the site of protonation in dihydrooxazine
species.
After extensive studies on the KR of nitroallylic amines 3a,12 an
organocatalyst 1 (50 mol %) was used to produce a
dihydrooxazine N-oxide intermediate 4a with a 47% yield and
excellent stereoselectivity (20:1 dr) (Table 1, entry 1). The
kinetically less reactive (S)-3a was recovered with a 51% yield
with 80% ee. The stable dihydrooxazine intermediate 4a acts as a
catalyst trap in the catalytic reaction. Subjection of various
aldehyde and nitroallylic amines under the same reaction
conditions resulted in stable heterocyclic nitronates 4 (Table 1,
entries 2−11). The absolute stereochemistry of the oxazine was
assigned unambiguously from the single crystal X-ray structural
analysis of 4b, and the stereochemistry of the nitroallylic amine
component was found to be R in the intermediate.13,14 The
Recently, various organocatalytic kinetic resolution (OCKR)
methods were developed to provide densely functionalized and
malleable enantioenriched substances.8 Previously, we reported
the KR of densely functionalized nitroallylic acetates and alcohols
through chiral enamine/iminium catalysis.9 We envisaged that
the KR of nitroallylic amines 3 would afford the enantioenriched
Received: February 20, 2016
© XXXX American Chemical Society
A
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Letter
incorporation in 6a at C3 when we carried out the experiment in
a mixture of 4-nitrophenol and D2O.
Table 1. KR of Nitroallylic Amines, Isolation and Hydrolysis
of Oxazine Intermedites
a
The optimized conditions were successfully employed for
diastereoselective protonation of other isolated oxazine inter-
mediates 4 to furnish corresponding THPs 6 with excellent
diastereo- and enantioselectivities (>20:1 dr and up to 98% ee)
(Table 1). The relative stereochemistry of the thermodynamic
products was established unequivocally from the X-ray structural
analysis of 6a, whereas the relative stereochemistry of kinetic
product 5a was assigned based on NOESY analysis (see SI).
Next, the enantioselective approach was attempted for
synthesizing THP 6 in a one-pot fashion through sequential
addition (see SI). The presence of the starting substrates, reactive
reagents, intermediates, and additives complicated the reaction.
The optimized reaction conditions provided the recovered
nitroallylic amine (S)-3a with 40% ee (45% yield) and product 6a
with 13:1 dr and 84% ee (40% yield), employing 4-nitrophenol
(50 mol %) and Et3N (20 mol %) (Scheme 2).13 The acid
e
2; 3
(S)-3
4
b
6
b
c
d
b
d
c
entry
yield /% ee
yield /dr
yield /dr /% ee
1
2a;3a
2a;3b
2a;3c
2a;3d
2a;3e
2a;3f
2a;3g
2a;3h
2a;3i
2a;3j
2b;3a
51/80
49/96
49/60
55/66
42/66
50/70
50/70
54/70
49/56
49/85
48/64
4a;47/20:1
4b;48/>20:1
4c;46/16:1
4d;33/10:1
4e;48/9:1
6a;83/>20:1/98
6b;90/>20:1/92
6c;86/20:1/92
6d;88/20:1/84
6e;89/19:1/90
6f;72/17:1/94
6g;89/>20:1/84
6h;84/>20:1/96
6i;84/20:1/86
6j;89/>20:1/88
6k;88/20:1/98
2
3
4
5
6
4f;48/>20:1
4g;43/12:1
4h;43/20:1
4i;39/20:1
4j;46/14:1
4k;50/8:1
Scheme 2. KR of Nitroallylic Amines in a One-Pot Operation
7
8
9
10
11
a
The reactions were carried out with 3 (0.2 mmol), 2 (0.12 mmol)
b
c
using 1 (0.1 mmol) at 0 °C in DCM. Isolated yield. Determined
d
1
from chiral HPLC analysis. Determined by H NMR crude analysis.
e
The reactions were carried out with isolated oxazine 4 using 4-
nitrophenol (50 mol %) in DCM at 25 °C.
additive facilitates diastereoselective protonation (followed by
oxazine hydrolysis) and the base additive maintains good
diastereoselectivities in products (5 vs 6). The eroded
enantioselectivity of the recovered (S)-3 was ascribed to the
base catalyzed racemization.
absolute stereochemistry of the antipodal recovered nitroallylic
amines was tentatively assigned an S configuration.
NMR studies revealed that the formation of the oxazine N-
oxide intermediate is spontaneous and the concentration of these
species reaches saturation within 10 min (Figure 1a).13 Next, the
To elucidate the details of the mechanism, we used density
functional theory (DFT) to explore several protonation
pathways for acid addition to species 4a. Pihko revealed that
the Si-face protonation proceeds preferentially on the C3 carbon
of the intermediate species with asynchronous ring opening.5b In
the present study, direct protonation of C3 in 4a by acids from
the Re-face and Si-face using 4-nitrophenol, acetic acid, and
hydronium ion was simulated. The corresponding energy
barriers were tabulated in Table 2. Substantial differences in
the energy barriers for protonation were identified using 4-
nitrophenol, where Si-face protonation was more than 20 kcal/
mol lower than that from the opposite face. Steric hindrance
introduced by -OTMS and -NHPh groups is believed to block
the incoming acid. Protonation by acetic acid and hydronium
Figure 1. (a) NMR profile of the reaction progress for KR process; (b)
progress of the oxazine hydrolysis and isomerization from kinetic (5a) to
thermodynamic (6a) product.
Table 2. Calculated ΔG‡TS (kcal/mol) for Protonation to 4a
hydrolytic ring opening reaction was studied. After vigorous
optimization of the hydrolysis conditions, we found that 4-
nitrophenol (50 mol %) was suitable for diastereoselective
protonation of nitronate in the oxazine 4a to provide
enantioenriched THP. The thermodynamic product 6a and
the regenerated catalyst 1 were formed steadily with the
hydrolysis of the oxazine 4a (Figure 1b). The concentration of
the initially formed kinetic product 5a diminished with time as it
was epimerized to the thermodynamic product 6a the trans-
formation of which was promoted by a base or even in situ
generated auxiliary alone. The oxazine hydrolysis is dependent
on the amount of 4-nitrophenol and the rate of protonation is
proportional to the acid loading up to 4.0 equiv (see Supporting
Information (SI)). In addition, we have observed deuterium
Using 4-Nitrophenol, Acetic Acid, and Hydronium
a
entry
acid (face of protonation)
ΔG‡TS
1
2
3
4
5
6
7
8
4-nitrophenol (Re-)
4-nitrophenol (Si-)
acetic acid (Re-)
acetic acid (Si-)
55.18
24.48
30.82
26.60
51.87
22.09
11.02
5.57
hydronium (Re-)
hydronium (Si-)
b
hydronium (Si-)
b
hydronium (Re-)
a
b
ΔG‡TS was estimated in respect to hydrogen bonded 4a. Using
intermediate of Seebach et al.5a
B
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Letter
also showed such face selectivity as listed in Table 2. The
hydrogen bonded 4-nitrophenol-4a complex and transition state
geometries of Re- and Si-face protonation are shown in Figure 2,
attempted to break the planar ring structure and reversibly
moved toward incoming acids. Charge analysis of such a flipping
mode suggested more negative charge accumulated at C3 as C3
moved away from the equilibrium position (see SI) and that
enhanced basicity would attract protons.
Under the acidic conditions, the stable intermediate 8 can be
converted to the substituted THP by sequential processes
(Scheme 3). The rds was believed to be the Si-face
Scheme 3. Mechanistic Investigation of the Reaction
Figure 2. Hydrogen bonded 4-nitrophenol and transition state
geometries of 4a from Re- (a and b) and Si- (c and d) face protonation.
in which the C4−O3 distance was substantially more elongated
for the Re-face conditions than the Si-face counterpart. For
comparison, Seebach’s intermediate in which C3 was connected
with a methyl group and was significantly accessible to external
incoming acids was calculated using H3O+ for protonation. The
corresponding predicted energy barriers for Re- and Si-face were
only 5.57 and 11.02 kcal/mol, respectively (Table 2, entries 7 and
8).
The electrostatic potential of the dihydrooxazine N-oxide
intermediate (4a) using its crystal structure showed the N-oxide
group to be the most nucleophilic region. Protonation at N-oxide
was determined to be more energetically favorable and
structurally accessible to the incoming acids (see SI). The stable
geometries of hydrogen-bonded 4a and incoming acid was
identified for 4-nitrophenol and acetic acid where hydronium was
found to protonate dihydroxazine N-oxide without any barrier.
Trace amounts of water could be attracted to the hydrophilic
groups, for example, N-oxide and CO2Et, near the C3 moiety.
Thus, a possible C3 protonation pathway from the protonated N-
oxide to C3 via a hydrogen-bond network was investigated. The
intermediates using two explicit water molecules along the
proposed reaction coordinate was shown (Figure 3). The barrier
diastereoselective protonation and the heterocyclic ring opening
by enlarging the C−O bond. These two events occurred
asynchronously. Further hydrolyzing the iminium ion and
cyclization/dehydration afforded the final THPs and regenerated
catalyst 1.
Next, we investigated the applications of (+)-6a, and to our
delight, this chiral enamine reacts in a highly diastereoselective
(>20:1 dr) path with N-chlorosuccinimide to furnish adduct 12a
in 81% yield, along with minor hydrolyzed product 13a (Scheme
4). This adduct 12a has a significance in mechanism perspectives,
Scheme 4. Synthesis of Fully Substituted Pipecolic Ester
Derivatives
as these adducts could be the probable intermediate species
involved in chiral enamine catalyzed α-chlorination of
aldehydes.3c,15 This kind of species cannot be isolated with the
linear aldehydes due to facile dissociation of the succinimide. For
the first instance, the probable intermediate species that were
involved in α-halogenation of aldehydes are isolated and
characterized with X-ray structural analysis.14 This is an
additional piece of evidence for the mechanism proposed by
Blackmond and co-workers on α-chlorination of linear
aldehydes.3c
The pipecolic acid derivatives prevail in numerous biological
and pharmaceutical molecules.16 In view of this, we found that 4-
nitrophenol is an appropriate acid additive for intermediate 12a
hydrolysis to afford five contiguous asymmetric centered
pipecolic ester motifs 13a including one quaternary halide
center in good yield (84%) with excellent stereoselectivities
(>20:1 dr and 98% ee) (Scheme 4). The relative stereochemistry
Figure 3. Schematic representation for H+ transferring from the
protonated N-oxide via hydrogen bond network to C3 is shown (from a
→ d). The relative energetics (kcal/mol) is listed in parentheses.
of such a pathway was predicted to be greater than 22.90 kcal/
mol, and the thermodynamically favored C3 protonation state is
lower than that of protonated N-oxide state (−1.01 kcal/mol).
Moreover, C3 protonation by 4-nitrophenol with the protonated
N-oxide (a two-proton transfer pathway) was also calculated, and
the corresponding barrier was predicted to be 36.09 kcal/mol
(see SI). These studies indicate that substantial energy barriers
(>20 kcal/mol) were found for the above protonation pathways
and this suggests the protonation process is the rds.
Vibrational analysis of this constrained-optimized geometry
identified the ring-opening vibration at 467 cm−1 in which C3
C
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Letter
(5) (a) Seebach, D.; Sun, X.; Sparr, C.; Ebert, M.-O.; Schweizer, W. B.;
Beck, A. K. Helv. Chim. Acta 2012, 95, 1064. (b) Sahoo, G.; Rahaman,
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́ ́
Angew. Chem., Int. Ed. 2012, 51, 13144. Also see: (c) Seebach, D.; Sun,
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of the hydrolyzed product 13 was assigned from X-ray structural
analysis of 13a.14 Surprisingly, N-bromosuccinimide furnished
corresponding adduct 12b and 12b′ in 1:1 dr with (+)-6a under
the same reaction conditions. Albeit, we obtained the hydrolyzed
product 13b in excellent diastereoselectivity (>20:1) after
hydrolysis.
In conclusion, we demonstrated a KR of densely function-
alized nitroallylic amines through isolation of the resting states
intermediates with excellent chemical yields and diastereo- and
enantioselectivities via the Michael reaction of aldehydes. These
isolated intermediates provided enantioenriched THPs upon N-
oxide protonation and subsequent diastereoselective protona-
tion/ring opening, followed by hydrolysis and dehydration. For
the first instance, computational studies have provided evidence
for nitronate oxygen atom protonation. The rds of diaster-
eoselective protonation and asynchronous ring opening is
compelling. Finally, we have provided an additional support
over the mechanism on α-chlorination of chiral enamines derived
from aldehydes and amines.
(6) For representative works, see: (a) Hayashi, Y.; Okamura, D.;
Yamazaki, T.; Ameda, Y.; Gotoh, H.; Tsuzuki, S.; Uchimaru, T.;
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(8) Gurubrahamam, R.; Cheng, Y.-S.; Huang, W.-Y.; Chen, K.
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(10) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation, Reactivity, and Synthetic Applications of Piperidine and Its
Derivatives; Elsevier: Amsterdam, 1991. (b) Cuthbertson, J. D.; Taylor,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00493.
Experimental procedures, X-ray data (PDF)
HPLC analysis; characterizations (PDF)
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
(11) For selected organocatalytic methods, see: (a) Blumel, M.;
̈
■
Chauhan, P.; Hahn, R.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 6012.
(b) Lin, H.; Tan, Y.; Liu, W.-J.; Zhang, Z.-C.; Sun, X.-W.; Lin, G.-Q.
Chem. Commun. 2013, 49, 4024. (c) Li, X.; Zhao, Y.; Qu, H.; Mao, Z.;
Lin, X. Chem. Commun. 2013, 49, 1401. (d) Shi, F.; Tan, W.; Zhu, R.-Y.;
Xing, G.-J.; Tu, S.-J. Adv. Synth. Catal. 2013, 355, 1605. (e) Shi, Z.; Yu,
P.; Loh, T.-P.; Zhong, G. Angew. Chem., Int. Ed. 2012, 51, 7825. (f) Huo,
L.; Ma, A.; Zhang, Y.; Ma, D. Adv. Synth. Catal. 2012, 354, 991.
(g) Wang, Y.; Zhu, S.; Ma, D. Org. Lett. 2011, 13, 1602. (h) Imashiro, R.;
Uehara, H.; Barbas, C. F. Org. Lett. 2010, 12, 5250. (i) Urushima, T.;
Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588.
(j) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu,
P.-F. Chem. - Eur. J. 2010, 16, 3922.
*E-mail: kchen@ntnu.edu.tw.
*E-mail: mktsai@ntnu.edu.tw
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the Ministry of Science and
Technology of Taiwan (MOST 102-2113-M-003-005-MY3 and
103-2113-M-003-005-MY2), and the authors are grateful to the
National Center for High-Performance Computing of Taiwan
for providing computer time and facilities.
(12) rac-3 were synthesized from their Morita-Baylis-Hillman alcohols.
Also, see: Rastogi, N.; Mohan, R.; Panda, D.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Biomol. Chem. 2006, 4, 3211. For the use
of primary nitroallylic amine in organocatalytic reaction, see: Wang, Y.;
Zhu, S.; Ma, D. Org. Lett. 2011, 13, 1602.
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