Regio- and Diastereoselective and Enantiospecific Metal-Free C(sp3)-H Arylation: Facile Access to Optically Active 5-Aryl 2,5-Disubstituted Pyrrolidines

Article abstract of DOI:10.1002/chem.201502297

Optically active 5-aryl 2,5-disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio- and diastereoselective and enantiospecific method for direct C-H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single-step three-component reaction under metal- and oxidant-free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin-converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp³ C-H arylation reaction. Preference for a given regio- and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re-aromatization step. The calculated energies reveals that the re-aromatization step is essentially rate determining, accompanying an activation barrier of Δ^≠G^S_L=25.6 kcal mol^-1. On arylated note: A novel, regio- and diastereoselective and enantiospecific direct C-H arylation reaction has been developed whereby enantiopure arylated pyrrolidines are synthesized in a single operation under metal- and oxidant-free conditions, starting from commercially available materials. The mechanistic pathway that results in high stereoselectivity is studied by using DFT.

Full text of DOI:10.1002/chem.201502297

DOI: 10.1002/chem.201502297
Full Paper
&
CÀH Activation
Regio- and Diastereoselective and Enantiospecific Metal-Free
3
C(sp )ÀH Arylation: Facile Access to Optically Active 5-Aryl
2
,5-Disubstituted Pyrrolidines
[a]
[a]
[b]
[b]
Surajit Haldar, Subhra Kanti Roy, Bholanath Maity, Debasis Koley,* and
Chandan K. Jana*
[a]
Abstract: Optically active 5-aryl 2,5-disubstituted pyrroli-
dines are the principal structural moiety of many bioactive
compounds including natural products and catalysts for
asymmetric synthesis. A highly regio- and diastereoselective
and enantiospecific method for direct CÀH arylation of ali-
phatic amine has been developed. Structurally diverse enan-
tiopure arylated pyrrolidines were synthesized from com-
mercially available starting materials, through a single-step
three-component reaction under metal- and oxidant-free
conditions. Furthermore, the complex analogous structure of
CCK antagonist RP 66803 and angiotensin-converting
enzyme inhibitors was easily constructed using the synthe-
sized arylated pyrrolidine derivative. Detailed theoretical cal-
culations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level)
were also carried to investigate the mechanism and high
3
level of stereocontrol involved in this direct sp CÀH aryla-
tion reaction. Preference for a given regio- and stereoselec-
tivity in the arylated product can be explained through elu-
cidation of the mechanism for dehydration, generating azo-
methine ylide, and for the final re-aromatization step. The
calculated energies reveals that the re-aromatization step is
essentially rate determining, accompanying an activation
°
S
L
À1
barrier of D G =25.6 kcalmol .
Introduction
and organic synthesis, demands the development of novel and
applicable methods for their preparation. Various methods
Arylated pyrrolidine serves as the key structural motif of many
have been reported for the synthesis of the arylated pyrroli-
[1]
[3–5]
natural and synthetic functional molecules. For some relevant
examples, they are present in different bioactive natural prod-
dines.
However, strategies for syntheses of these molecules
in enantiomerically pure form are limited. Chiral auxiliary-based
[1d]
[1e]
[6]
ucts like prolinalin B, (À)-codonopsinine, and radicamine
(Figure 1). Moreover, many medicinally important synthet-
strategies were mainly employed in this regard. In addition,
[1f,g]
[7]
B
a few enantioselective strategies were also applied. However,
ic molecules are built on arylated pyrrolidine. Enantiopure 5-ar-
ylproline derivative is the core unit of CCK antagonist (RP
primarily multistep N-cycloalkylation strategies involving chiral
[
1h]
[1i,j]
6
6803),
angiotensin-converting enzyme (ACE) inhibitor
[1k]
and Schramm’s C-azanucleoside having potential trypanoso-
mal activity. Other than pharmacological applications, enan-
tioenriched arylated pyrrolidine based molecules have impor-
tant value in organic synthesis. They are either used directly or
in the presence of metal catalyst to promote asymmetric reac-
[
2]
tions. The obvious widespread application of enantioenriched
arylated pyrrolidine derivatives, in both medicinal chemistry
[
a] S. Haldar, S. K. Roy, Prof. Dr. C. K. Jana
Department Of Chemistry, Indian Institute of Technology Guwahati
Guwahati-781039, Assam (India)
E-mail: ckjana@iitg.ernet.in
[
b] B. Maity, Prof. Dr. D. Koley
Department of Chemical Sciences,
Indian Institute of Science Education and Research Kolkata
Mohanpur-741246 (India)
E-mail: koley@iiserkol.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502297.
Figure 1. 5-Aryl 2,5-disubstituted pyrrolidines in bioactive molecules.
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Scheme 1. Syntheses of optically active 5-aryl 2,5-disubstituted pyrrolidines.
Scheme 2. a) Challenges and opportunity of direct CÀH arylation of substi-
tuted pyrrolidine; b) arylation of l-proline methyl ester.
amines were adopted for syntheses of enantioenriched 2,5-dis-
[8,2e]
ubstituted pyrrolidines (Scheme 1).
A diastereoselective car-
[
9]
boxylation involving stoichiometric amount of chiral reagent
[10]
[a]
and a diastereoselective Heck arylation were developed to
obtain the 2,5-disubstituted pyrrolidine, albeit with moderate
yield and selectivity. An asymmetric hydrogenation strategy
was also employed for reduction of substituted pyrrole under
Table 1. Optimization of the reaction condition.
[11]
high pressure of hydrogen. The main drawback of known
protocols, with a view to their practical application, originates
from their multistep reaction sequences, often with moderate
diastereoselectivities. We report herein the first example of
metal- and oxidant-free highly regio- and diastereoselective
[
b]
Entry
Activator
Solvent, Temp.
Time
Yield [%]
1
2
10
10
10
10
12
12
12
12
12
12
12
12
12
THF, reflux
THF, reflux
48 h
78 h
66 h
40 min
66 h
37
65
59
46
56
71
53
65
31
[c]
3
3
4
5
6
7
8
9
1
benzene, reflux
toluene, mw, 1508C
THF, reflux
benzene, reflux
toluene, mw, 1508C
toluene, mw, 1508C
xylene, mw, 1708C
and enantiospecific direct sp CÀH arylation to access
enantioenriched 2,5-disubstituted pyrrolidine derivatives
(
Scheme 1).
72 h
30 min
40 min
40 min
40 min
40 min
40 min
40 min
During our ongoing investigations into direct functionaliza-
[12]
tion of aliphatic amines, we developed a method for direct
CÀH arylation of pyrrolidine by a simple three-component re-
0
CH
3
CN, mw, 1008C
20
[5l]
action under metal- and oxidant-free conditions. Almost at
the same time, a similar report was published by Seidel and
11
DCM, mw, 608C
EtOH, mw, 1008C
benzene, mw, 1008C
trace
trace
12
12
[
5m]
13
co-workers.
However, no report on stereoselective CÀH ary-
lation of substituted pyrrolidine to access enantiopure 2,5-dis-
ubstituted pyrrolidine was reported to date. The possibility to
obtain enantioenriched 2,5-disubstituted pyrrolidines by direct
CÀH functionalization of commercially available starting mate-
rials will be of particular interest in the context of finding new
bioactive compound and chiral scaffold for asymmetric cataly-
sis. However, readily available enantiopure proline loses its
chirality due to decarboxylation during the arylation reac-
[a] Reactions were carried out with prolinol 9 (0.3 mmol), 2-naphthol
0.25 mmol), and 9-fluorenone 10 (0.3 mmol) or its imine derivative 12.
b] Yields of isolated product. [c] Prolinol (3.0 equiv) was used in excess.
(
[
[
5h–j]
tion.
Experimental Results and Discussion
General notes on direct CÀH arylation reaction
Generally, during direct CÀH arylation of substituted N-hetero-
cycle 1, reaction should overcome regio- and diastereoselectiv-
ity issues to avoid forming a mixture of diastereoisomers 2, 3
and 4 (Scheme 2a). The use of enantiopure starting material,
aiming for enantioenriched product, put further challenges
due to the possibility of racemization that may allow formation
Figure 2. ORTEP representations of representative compounds 11 f, 11 g, 11 l
and 13a showing relative syn stereochemistry. Thermal ellipsoids are set at
30% probability.
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of a mixture of six isomers. Preferences for the formation of
the less-substituted enamine, to avoid the allylic strain that
exists in its more substituted isomer, have been well docu-
the reaction further to improve the yield. Higher reaction time
(78 h) increased the chemical yield to 65% (Table 1, entry 2). Ef-
forts were then continued to decrease the reaction time. We
anticipated that the reaction time could be reduced by pro-
moting the reaction of secondary amine and carbonyl com-
pound. Therefore, we employed 9-fluorenone imine 12 instead
of 9-fluorenone to facilitate the reaction more effectively. A
maximum yield of 71% of the desired product was obtained
after 72 h (Table 1, entry 6). Moreover, a 53% yield was ob-
tained in 30 min when the reaction was carried out at 1508C
in toluene under microwave irradiation (Table 1, entry 7). At
the same time, the reaction was highly stereoselective, provid-
ing 11 a as the sole isomer with unaltered enantiopurity. The
yield was further increased to 65% by increasing the reaction
time to 40 min (Table 1, entry 8). The effects of varying other
reaction conditions, such as solvent, temperature, and carbonyl
compound (activator), were also examined. A trace amount of
the product was obtained when using protic and low-boiling
solvents (Table 1, entry 11 and 12). Other activators, such as
benzophenone, anthrone, and anthraquinone, which are analo-
gous to 9-fluorenone, failed to produce the corresponding CÀ
H-arylated compounds. Thus the reactions using 9-fluorenone
imine in benzene under reflux and in toluene at 1508C for
[
13]
mented. Therefore, we anticipated that the isomerization of
the initially formed iminium ion 5 could be preferentially
drawn towards 6 due to the unfavorable allylic strain in its re-
gioisomer 7. Thus the selective formation of 6 will solve the re-
gioselectivity issue, as well as the racemization problem. The
remaining facial selectivity can be controlled by tuning the
nature of Ar, R, and CHAr’Ar’ (PG) to afford one isomer selec-
[
14]
tively. It was thought that the ester derivative of proline may
be used to avoid decarboxylation during the direct CÀH aryla-
tion reaction. However, decarboxylation was found even in a re-
action of l-proline methyl or ethyl ester, providing arylated
pyrrolidine 8 (Scheme 2b).
Evaluation of reaction conditions
We started our investigation with the attempt to functionalize
commercially available enantiomerically pure (S)-prolinol 9. To
start with, enantioenriched prolinol reacted with 9-fluorenone
10 in tetrahydrofuran under reflux condition in the presence of
2
-naphthol as a potential nucleophile. After 48 h, the desired
4
0 min under microwave irradiation were found to be superior
product 11 a was isolated in 37% yield as a single diastereoiso-
mer (Table 1, entry 1). The relative syn stereochemistry was as-
signed in analogy of the stereochemistry observed from the
single crystal X-ray structures of 11 f, 11 g, and 11 l (Figure 2).
To our delight, we also found that the chiral center of starting
prolinol 9 was retained to provide 11 a with >99% enantio-
meric excess. This encouraging finding led us to investigate
for this CÀH arylation process.
Substrate scope of the direct CÀH arylation reaction
We then utilized the optimized reaction conditions to investi-
gate the substrate scope. Different electron-rich aromatic com-
Scheme 3. Substrate scope of arylation reaction; [a] reactions were carried out with racemic amine.
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pounds were used for the direct CÀH functionalization of proli-
nol and 2-methyl pyrrolidine (Scheme 3). Naphthols and their
derivatives reacted smoothly, providing different 2,5-disubsti-
tuted pyrrolidine derivatives (11 b–e and 13a–e) with very
good yields and excellent stereoselectivities. Aside from naph-
thols, phenol derivatives and 4-hydroxycoumarin were also
employed as the effective nucleophiles producing CÀH-func-
tionalized derivatives (11 f–m, 15, and 13 f–k). Functional
groups that are sensitive towards transition metal- and oxi-
dant-mediated reaction were well tolerated in this reaction.
Two regioisomeric products 13j and 13k were isolated when
chrysin was used as the nucleophile. The best yield (90%) of
arylated pyrrolidine derivative 11 l was obtained when a highly
oxygenated phenol derivative, sesamol (14), was employed as
the nucleophile. Similarly, arylated amine 15 was obtained with
6
5% yield and >99% ee through arylation of 2-methoxymeth-
yl pyrrolidine.
In all cases, the products were isolated as the single diaste-
reoisomer. The relative syn orientation of the aryl and alkyl
groups in 11 f, 11 g, 11 l and 13a were confirmed from their
corresponding molecular structures obtained via the single
Scheme 4. Syntheses of chiral amines and their synthetic applications.
[15]
crystal X-ray diffraction analysis (Figure 2). During the CÀH
arylation of enantiopure (S)-pyrrolidine methanol and its deriv-
atives, arylated compounds were found by HPLC analysis to
have excellent enantiopurities. Optically pure arylated com-
pounds (ent-11 l and ent-15) were also obtained from (R)-pyrro-
lidine methanol and its O-methylated derivatives. Analogous
retention of the chiral center occurred during the arylation of
enantioenriched (R)-2-methylpyrrolidine, providing 5-aryl 2-
methylpyrrolidines with excellent enantiopurities (>99%).
However, indole derivatives, the most widely used nucleophilic
aromatic substrates, were unable to provide acceptable yields
of the corresponding CÀH arylated compounds under these
conditions, indicating that the phenolic OH plays an important
role in the reaction.
afford the dipeptide 19 (63%). Similarly, urea derivative 20,
prepared from glycine in 92% yield, was coupled with 18 to
provide dipeptide 21, which structurally resembles biologically
important dipeptides such as RP 66803 and ACE inhibitors.
Computational Results and Discussion
DFT calculations were performed at M06-2X/TZVPP/SMD//M06-
2
X/6-31+G(d,p) level of theory (see computational details in
the Supporting Information) to illustrate the origin of regio-
and stereoselectivity in the reaction of (S)-prolinol 9 with sesa-
mol 14 in the presence of 9-fluorenone 10. Three possible iso-
meric product, 11 l, 3l, and 4l, corresponding to 2, 3 and 4 re-
spectively, can be formed in this CÀH arylation reaction
Synthesis and derivatization of chiral amines
Enantiopure N-fluorenyl 2,5-disubstituted pyrrolidine
derivatives, which were obtained by this method, can
be used directly as the chiral ligand in metal-cata-
[2]
lyzed asymmetric reactions. Further modification to
form the free amine would open an important
avenue in finding new bioactive compounds and
chiral scaffolds for asymmetric catalysis. For N-de-
fluorenylation, the pyrrolidine derivative 11 a was
subjected to hydrogenolysis conditions to give the 5-
aryl prolinol 16 with 65% yield and with retention of
enantiomeric excess (>99% ee; Scheme 4). Similarly,
compound 13a provided the corresponding secon-
dary amine 17. The corresponding phenyl derivative
of 16 was prepared by a linear 10-step synthetic se-
[8e]
quence in the context of the synthesis of RP 66803.
The primary hydroxy group was selectively silylated
Scheme 5. Proposed mechanism of the overall reaction. The respective energy terms (in
under standard conditions to provide silyl ether 18
À1
°
S
kcalmol ) below the arrows and in parenthesis are activation barrier (D G ) and relative
L
(
66%). The enantioenriched 5-arylated prolinol 18
S
L
free energy (DG ) with respect to the starting materials at M06-2X/TZVPP/SMD//M06-2X/
then reacted efficiently with Boc-protected glycine to 6-31+G(d,p) level.
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[
16]
(
Scheme 2a and Scheme S1 in the Supporting Information).
celerated in presence of sesamol, since the accompanying six
The reaction pathway (Scheme 5) obtained from the calculated
results consists of following two steps: I) nucleophilic attack of
member transition state, I–II encounters a low activation barri-
°
S
À1
er (D G =14.1 kcalmol , Figure 3 and Scheme 5). The result-
L
9
on 10 followed by dehydration to generate azomethine
ing hemiaminal II then undergoes dehydration to generate
ylide III. The dehydration process requires the protonation of
II, giving rise to an iminium ion II-OH (see the Supporting In-
formation, Figure S1). Unfortunately this step is highly ender-
ylide (III) and II) nucleophilic attack of 14 at the iminium ion
center (C , Figure 3) to deliver intermediates IVt/IVc, which can
finally re-aromatize to furnish the desired product.
2
À1
gonic by 58.7 kcalmol , since the ionic species formed are de-
stabilized in a nonpolar toluene environment. However, sesa-
mol-assisted dehydration in a concerted manner requires ac-
Step I
1
1
°
S
À1
In the initial step, nucleophilic addition of N ÀH of 9 to the
cessible activation barrier (D G =23.6 kcalmol ) for the tran-
L
3
2
carbonyl group, C =O of 10 via a four-membered cyclic transi-
tion state (9–10 in Figure 3) requires high activation barrier of
sition state II–III (Figure 3). The geometry of the transition
state reveals that sesamol donates a proton to the OH group
À1
À1
3
3
7.0 kcalmol , which is similar to the value of 32.5 kcalmol
at C to liberate water with concomitant acceptance of
2
previously reported by Yu and co-workers in their investigation
a proton from the C center. The water molecule has already
[17]
3
1
3
of the formation of N-alkyl pyrroles. However, this step is ac-
been decoordinated from C and the N ÀC bond (Figure 3) is
À1
Figure 3. a) Energy profile [in kcalmol at M06-2X/TZVPP/SMD//M06/6-31+G(d,p) level] for the nucleophilic attack of 9 on 10 followed by dehydration in
the presence of 14. Square dotted and solid lines represent the formation pathways of ylides III and III’, respectively. The round dotted line shows the energy
profile for 9-fluorenone imine 12; b) optimized geometries of transition states at M06-2X/6-31+G(d,p) level involve in this step.
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À
shortened by 0.15 Š (II!II–III) in the transition-state geometry.
(RO ) fragment giving rise to either of the stereoisomeric inter-
The resulting ylide III is less stable than the reactants by
mediates IVc or IVt (Figure 4a).Therefore, the favorable route
may follow the initial protonation at C and subsequent nucle-
À1
3
1
3.5 kcalmol , indicating its enhanced reactivity in the pres-
2
ence of a nucleophile. A concerted pathway that generates re-
ophilic attack at C in a single step, concerted fashion
2
1
gioisomer III’ from II is highly unlikely, since the H at C is anti
(Figure 4). Depending on the approach of sesamol, formation
of two isomeric intermediates IVc and IVt can be envisaged.
III-IVc and III-IVt represents the respective transition states ac-
2
7
3
to the O H group at C (Figure 3). Therefore, another isomer
of II, that is, II’, is necessary to undergo the sesamol-assisted
dehydration process to furnish isomer III’. Unsurprisingly, the
transformation II’!III’ has a high activation barrier of 36.6 kcal
À1
companying energy barriers of 18.4 and 14.2 kcalmol respec-
tively. In both cases, the imaginary frequencies correspond to
À1
3
3
mol (see the Supporting Information, Figure S1) because,
the combined mode of proton transfer from O to C and con-
2
3
4
2
unlike II!III the H atom is less positive than H in II/II’(q
H2/H3
=
comitant C ÀC bond formation (Figure 4b).
0
.12/0.21 e; see the Supporting Information, Table S1). Since
Finally, re-aromatizations of IVc and IVt generate the respec-
tive CÀH arylated products 11 l and 3l (Figure 5 and Figure S3
in the Supporting Information). Several pathways for re-aroma-
formation of the intermediate III’ requires comparatively high
energy, we have not considered the subsequent steps leading
to regioisomer 4l in this study
(
see the Supporting Information,
[
16]
Scheme S1).
Encouraged by
the experimental findings, we
performed an additional investi-
gation using the imine analogue
12 as an alternative activating
agent. Employing 12, we report
a low lying pathway accessible
for the formation of III (round
dotted line in Figure 3). This
result explains the experimental
finding of faster rate in the pres-
ence of 12.
Step II
The next step could proceed via
protonation followed by nucleo-
philic attack of sesamol at the
zwitterion III. NBO (Natural Bond
3
Orbital) results indicate that C is
2
more electron rich than C of the
pyrrolidine fragment in ylide III
(
q
C3/C2
=À0.029/0.077 e; see the
Supporting
Information,
Table S1). This electronic ar-
rangement is further supported
by the Kohn–Sham (KS) frontier
orbitals (see the Supporting In-
formation, Figure S3). The HOMO
3
of III is mostly contributed by C
3
2
(
C : 38%, C : 18%) whereas the
2
2
LUMO of III is centered at C (C :
1
3
4
5%, N : 17%). Protonation at C
of III leads to a more unstable
ionic species, III-P. The endergo-
S
L
À1
nicity (DG =43.3 kcalmol ) is
due to the formation of an ionic
species that is destabilized in
nonpolar toluene medium. The
reactive III-P can immediately
Figure 4. a) Energy profile for nucleophilic addition of 14 to III. Solid and square dotted lines are for concerted
pathways of IVc and IVt formation, respectively and dashed dotted line shows stepwise protonation followed by
nucleophilic attack; b) optimized geometries of transition states involved in this step. For energy and other con-
combine with the sesamolate ventions, refer to Figure 3.
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tization have been investigated; the results are collected in
in Figure 3) depicting this exchange entails a lowest activation
4
3
À1
Figures 5 and S3. In the first case, proton transfer from C to O
following keto-enol tautomerism requires high-energy transi-
barrier of 25.6 kcalmol . Unfortunately, a similar route is un-
likely for IVt as the incoming sesamol is oriented anti to the
°
S
L
À1
1
5
tion states, [D G (IVc-ts/IVt-ts)=54.2/54.1 kcalmol ; Figure 5,
CH O H group (see the Supporting Information, Figure S3).
2
18
d] since such 1,3-hydride shift is known to be forbidden.
From the calculated energies represented in Scheme 5 and
Figures 3–5, the re-aromatization step is essentially rate deter-
mining. On the basis of kinetic investigations, Forlani et al. re-
ported a similar finding whereby the step involving re-aromati-
zation is rate limiting in the aromatic electrophilic substitution
Secondly, any possibility of an intermolecular proton exchange
from external sesamol can also be ruled out due to high
°
S
L
À1
energy barriers [D G (IVc-ts1/IVt-ts1)=39.6/36.8 kcalmol ;
Figure 5, g]. Interestingly, in a similar 1,3-H shift where the
6
4
1
[19]
H is shared between C and N in the transition states, the ac-
reaction. The lowest energy route for formation of 11 l is via
tivation barriers for this step are reduced to moderate energy
the intramolecular proton exchange involving the distorted
six-membered transition state IVc–11 l. On the other hand, the
lowest energy path for IVt!3l transformation is via transition
state IVt-ts2 (see the Supporting Information, Figure S3, a).
Clearly the formation of 11 l is more favorable than 3l by
°
S
values compared to previous pathways[D G (IVc-ts2/IVt-ts2)=
L
À1
2
8.1/33.7 kcalmol ; Figure 5, a]. The imaginary mode for
these two transition states involves the proton transfer from
4
1
the C to the N center (Figure 5b). Most importantly, these
transition states transform into the respective products 11 l
and 3l during IRC (Intrinsic Reaction Coordinate) optimizations.
However, it is interesting to note that even though the two
transition states IVc-ts2 and IVt-ts2 show similar atomic rear-
À1
8.1 kcalmol , which is in accordance with experimental obser-
1
5
vation. Therefore, we can justify that CH O H plays a significant
2
role in furnishing the cis product (11 l) via intramolecular
proton exchange.
°
S
rangements, the relative activation barrier (DD G ) accompa-
We also explored possibilities with other substituents, such
L
À1
nying them is 5.6 kcalmol . It is observed that in IVt the lone-
pair occupancy on N (1.822 e) is reduced due to hyperconju-
as a methyl group instead of the CH OH unit in 9. Herein, we
2
1
have not considered step I of the reaction for the Me-substitut-
2
4
gation from the neighbouring H and H atoms (Figure 5). A
ed analogue of 9, since the CH OH group doesn’t play an addi-
2
similar situation is also present in IVc, although to a lesser
extent, where the hyperconjugation is only effective with H ,
tional role in this step. Therefore, we will directly discuss
step II, originating from ylide intermediate III-Me. Similar reac-
tion steps to those for III are followed by III-Me (for energy
profiles, see the Supporting Information, Figures S4 and S5).
2
leading to a higher lone-pair occupancy on nitrogen (1.861 e).
Therefore, the transition state involving proton transfer to-
1
1
wards N is facilitated for IVc rather than IVt. The shorter N À Analogous cis- and trans-isomeric products resulting from the
2
C
bond length in IVt than IVc [r
1
2
(IVc/IVt)=1.56/1.43 Š]
coupling of sesamol with III-Me are 13h and 3h respective-
N ÀC
[
16]
supports indirectly the magnitude of this hyperconjugative
ly. Not surprisingly, the re- aromatization step is rate limiting.
effect. From IVc, there remains another possibility for intramo-
lecular proton exchange between O H ··O /C H ··O partners.
The highest activation barrier for 13h formation is 5.0 kcal
1
5
3
4
6
1
À1
mol lower than the corresponding step involved in 3h for-
°
S
À1
The distorted six-membered transition state IVc–11 l (solid line
mation
[D G (IVc-ts2-Me/IVt-ts1-Me)=30.3/35.3 kcalmol ,
L
Figure 5. a) Energy profile for re-aromatization of IVc. Each line represents a different route of re-aromatization step (see text); b) optimized geometries of
transition states. For energy and other conventions, refer to Figure 3.
Chem. Eur. J. 2015, 21, 15290 – 15298
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solid/dashed line in Figure S4/S5, c/a]. Notably, substitu-
Acknowledgements
tion of CH OH by Me follows a similar mechanistic scenario,
2
providing a clear advantage for formation of the cis- isomeric
product. The relative activation barrier for the stereoisomeric
product formation in the presence ofthe Me substituent is
S.H. and S.K.R. are thankful to IITG for fellowships. B.M. is
thankful to the CSIR for an SRF fellowship. D.K. acknowledges
the IISER-Kolkata for a start-up grant and the CSIR for project
funding (01(2770)/13/EMR-II). C.K.J. acknowledges SERB, New
Delhi (EMR/2014/001176) for funding and CIF, IITG for analytical
facilities. We thank the group of Prof. S. C. Pan for kindly allow-
ing us to use one of their chiral columns.
°
S
lower than that with CH OH (DD G (Me/CH OH)=5.0/8.1 kcal
2
L
2
À1
mol ), indicating the effect of the latter in stabilization of the
IVc–11 l transition state (see above).
Reaction in ethanol
Keywords: amines · arylation · CÀH activation · density
functional calculations · stereoselectivity
In polar media like ethanol, the reaction prefers alternate
routes at two particular steps: dehydration of II and nucleo-
philic attack at III. Dehydration of II results in ionic species,
whose formation is accelerated in polar media. However these
species are prone to deactivation through coordination of
other nucleophiles present in the medium. During this step,
both ethanol (the solvent in this case) as well as sesamol can
act as proton donors to form the ionic species II-OH (see the
Supporting Information, Figure S1). However, the sesamol-as-
sisted pathway (see the Supporting Information, Figure S1,
c) is more favorable than the ethanol-assisted one (a) by
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À
1
7.3 kcalmol , because the conjugate base of sesamol (RO )
À
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3
cleophilic attack of EtO at C of II-OH evidently forms a stable
intermediate III-OEt, which is 4 kcalmol less stable than inter-
À1
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À1
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Conclusion
1
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In summary, highly regio- and stereoselective and enantiospe-
cific direct CÀH arylation of substituted pyrrolidine was ach-
ieved under metal- and oxidant-free reaction conditions, pro-
ducing a variety of syn-2,5-disubstituted pyrrolidines with ex-
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regioselectivity, and racemization were controlled to provide
one out of six possible isomers. Optically active arylated pyrro-
lidine was shown to be useful for the easy and efficient synthe-
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mechanistic route for the selective CÀH arylation reaction, cor-
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Received: June 12, 2015
Published online on September 7, 2015
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim