Formal aromaticity transfer for palladium-catalyzed coupling between phenols and pyrrolidines/indolines

Article abstract of DOI:10.1039/c7sc02578e

We herein describe a palladium-catalyzed formal aromaticity transfer coupling reaction between phenols and pyrrolidines or indolines to generate the corresponding N-cyclohexyl pyrroles or indoles. In this transformation, the aromaticity of phenols is formally passed on to the pyrrolidine or indoline units. Substituted phenols thus can serve as latent cyclohexyl equivalents for the fast construction of various N-cyclohexyl pyrroles and indoles.

Full text of DOI:10.1039/c7sc02578e

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Formal Aromaticity-Transfer for Palladium-Catalyzed Coupling
between Phenols and Pyrrolidines/Indolines
Zihang Qiu,a Jiang-Sheng Lib and Chao-Jun Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We herein describe a palladium-catalyzed formal aromaticity- hydrogenation conditions (Scheme 1, b),7k which was also
transfer coupling reaction between phenols and pyrrolidines or successful in a flow reactor.8 Later, a formal direct-coupling of
indolines to generate the corresponding N-cyclohexyl pyrroles or phenols with amines to generate aromatic amines was realized
indoles. In this transformation, the aromaticity of phenols is via an in situ hydrogenation-dehydrogenation (“H-borrowing”)
formally passed on to the pyrrolidines or indolines units. strategy to maintain the aromatic nature of the starting phenol
Substituted phenols thus can serve as latent cyclohexyl ring overall (Scheme 1, c).7j Inspired by these early successes,
equivalents for a fast construction of various N-cyclohexyl pyrroles we are intrigued by the possibility of aromaticity-transfer
and indoles.
reaction between phenols and pyrrolidines/indolines to afford
the N-cyclohexyl pyrroles/indoles (Scheme 1, d). Both atom-
economy9 and redox-economy10 are highlighted in such
transformation since the aromaticity of phenols will be further
reinstalled into the pyrrolidine or indoline motifs in this
process. Furthermore, the aromaticity-transfer products, N-
cyclohexyl pyrroles/indoles, are valuable units in various bio-
active molecules such as antitumor, antibacterial, and antiviral
agents.11
Phenols are widely available and can be obtained at low cost
from nature, since they comprise one of the basic units in the
lignocellulosic biomass as well as coal.1 Therefore, phenols are
ideal aromatic coupling partners and cyclic C-6 feedstocks
because of their renewable and sustainable profiles. Past
decades have witnessed tremendous progress of the cross-
coupling (C-O bond cleavage) of phenol derivatives, pioneered
by Shi,2 Chatani,3 Martin4 and others.5 In addition, phenols can
potentially be used as cyclohexyl synthons due to their facile
reduction, in which cyclohexanone or cyclohexenone can be
obtained under controlled hydrogenation conditions.6 The
combination of their reductive and renewable features led to
increasing interests in the selective reduction and
transformation of phenols and cyclohexanones or
cyclohexenones (the reduced forms of phenols) in recent
years.7
H2O
R
O2
R
R
2. Reduction of aromaticity
OH
H
N
N
cat. Pd/C (7 mol%)
6 equiv HCO2Na
N
+
+
+
H2O (b)
R
Previously, we and others developed a homogeneous
palladium-catalyzed “oxidative aromatization process” to
synthesize aromatic amines utilizing cyclohexanone or
cyclohexenone as cyclic-aromatic synthons (Scheme 1, a).7g, 7l
Recently, a reductive coupling reaction between phenols and
amines to form cyclohexylamines was succeeded using
phenols as cyclohexyl synthons under Pd/C-catalyzed transfer
3. Maintaining of aromaticity:
OH
H
cat. Pd/C (10 mol%)
N
+
0.5 equiv TFA
1.5 equiv HCO2Na
R
H2O
(c)
R
B. This work: Transfer of Aromaticity
OH
H
N
N
+
(d)
H2O
+
R
R
Scheme 1. Design of the aromaticity-transfer reaction.
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Table 1 Optimization of the reaction conditions[a]
scope initially, unfortunately, we found that the conversion of
phenols was low
Table 2 Substrate scope of phenols[a]
Pd/C (10 mol%)
OH
H
N
NaBH4 (50 mol%)
N
+
entry
hydride
source
(mol%)
acid
(mol%)
T
Yield
(%)
4
TfOH (25 mol%)
R
R
1,4-dioxane, 150 o
C
(oC)
1
2a
3
3a
9
5
32
14
6
1[b]
2
HCO2Na (150)
HCO2Na (150)
HCO2Na (150)
HCO2Na (150)
HCO2Na (150)
HCO2Na (150)
HCO2Na (200)
HCO2Na (200)
HCO2Na (200)
NaBH4 (50)
-
-
140
140
140
140
140
160
160
160
150
150
150
150
27
41
43
20
8
R1 = 2-Me, 3b, 85%, cis/trans = 1/4.8
R1 = 3-Me, 3c, 76%[b], cis/trans = 6.5/1
R1 = 4-Me, 3d, 79%, cis/trans = 1/4.9
R1 = 3-Et, 3e, 80%[b], cis/trans = 5.8/1
R1 = 4-Et, 3f, 94%, cis/trans = 1/5.3
R1 = 4-iPr, 3g, 71%, cis/trans = 1/7.9
R1 = 4-tBu, 3h, 70%, cis/trans = 1/16
R1 = 3-tBu, 3i, 63%, cis/trans = 18.8/1
31
N
N
3
PhCO
2
H (50)
23
R1
4
TFA (50)
56
13
10
2
3b-3i
3a, 80%
(43%)[c]
5
TfOH (50)
TfOH (50)
TfOH (50)
TfOH (100)
TfOH (100)
TfOH (100)
TfOH (50)
TfOH (25)
69
6
71
13
20
7
7
61
9
8
77
7
N
N
N
9
75
5
11
18
10
4
O
10
11
12
40
20
5
O
O
OEt
3l, 59%,
cis/trans = 1/3.5
NaBH4 (50)
71
3k, 72%,
cis/trans = 2.4/1
3j, 51%,
cis/trans = 1/1.5
NaBH4 (50)
80 (80)
8
[a] Reaction conditions: phenol (0.2 mmol, 1 equiv), pyrrolidine (0.28 mmol, 1.4
equiv), 10 mol% of 5 wt% Pd/C, acid with hydride source in 1,4-dixoane (1 mL)
were stirred under argon in 10-mL sealed tube for 12 h; NMR yields were given
with 1,3,5-trimethoxylbenzene as the internal standard, with isolated yield given
in parentheses; [b] Toluene was used as the solvent. For details of optimization,
please see the supporting information (SI); TFA = trifluoroacetic acid; TfOH =
trifluoromethanesulfonic acid.
N
N
F3C
N
O
O
AcHN
3o, 90%,
3n, 50%,
cis/trans = 8.8/1
3m, 90%,
cis/trans = 1/4.5
cis/trans = 1/2.9
N
N
To investigate the feasibility of our hypothesis, we initially
tested the reaction of phenol with pyrrolidine by using Pd/C as
the catalyst, 1.5 equiv HCO2Na as the hydride source and
toluene as the solvent at 140 oC (Table 1, entry 1). Gratifyingly,
the desired aromaticity-transfer product N-cyclohexyl pyrrole
PhHN
HO
N
AcHN
O
3p[b], 43%,
3q[b], 47%,
3r, 49%
cis/trans = 1/3.8
cis/trans = 1/4.5
cis/trans = 1/11.8
O
N
N
(
3a) could be obtained in 9% NMR yield along with the two by-
OMe
NHAc
products: the direct cross-coupling product, N-phenyl pyrrole
N
(
(
4
), as well as the net reduction product, N-cyclohexylamine
). strong solvent effect was observed in this
3s, 60%,
isomer ratio: 1:0.10:0.08
3u
, 34%
3t, 41%,
isomer ratio:1:0.66:0.37
5
A
cis/trans = 1/3.5
transformation. When dioxane was used as the solvent instead
of toluene (Table 1, entry 2), the yield of desired product 3a
was significantly increased to 31%. Since acids can promote
the condensation of ketone with amine, various acids were
evaluated (Table 1, entries 3-5 & see supporting information
(SI), Table S1). Generally, Brønsted acids worked better than
Lewis acids (Table S1) and among all the Brønsted acids
examined, stronger acids gave better results than weaker
acids. Following this trend, TfOH showed the best efficiency,
generating the desired product in 69% NMR yield (Table 1,
entry 5). Elevating the reaction temperature from 140 oC to
160 oC slightly increased the desired product yield (Table1,
entry 6). Increasing the amount of HCO2Na from 1.5 equiv to
2.0 equiv decreased the yield slightly; however, when the
amount of TfOH was simultaneously increased from 0.5 equiv
to 1.0 equiv, the yield was improved to 77% (Table 1, entries 7-
8). This might suggest that a balanced combination of acidity
and hydride donor amount was essential in this reaction
system. Lowering the temperature from 160 oC to 150 oC
showed similar reaction efficiency (Table 1, entries 8-9). When
we tried to use the entry 9 conditions to explore the reaction
[a] Reaction conditions: phenols (0.2 mmol, 1 equiv), pyrrolidine (0.28 mmol, 1.4
equiv), Pd/C (10 mol%), NaBH4 (50 mol%), TfOH (25 mol%) in 1,4-dioxane (1 mL)
were stirred at 150 oC under argon in 10-mL sealed tube for 12 h; isolated yields
were given unless otherwise noted; cis/trans (isomer) ratio was determined by
crude 1H NMR. [b] 62.5% NaBH4 was used. [c] 3-Methoxyphenol was used as
substrate and NMR yield was given with 1,3,5-trimethoxybenzene as internal
standard.
with phenols bearing bulky substituents, such as 3-tert-butyl-
phenol. To overcome this problem, NaBH4, which is a stronger
hydride donor than HCO2Na,12 was used as the hydride source
to re-examine the reaction system (Table 1, entries 10-12 &
Table S2). Ultimately, by carefully selecting the combination of
acid and the amount of NaBH4 (Table S2), the desired product
could be obtained in 80% yield (Table 1, entry 12).
With the optimized conditions in hand, the substrate scope
of phenols was explored next. As shown in Table 2, various
alkyl substituted phenols reacted smoothly to afford the
corresponding products in moderate to excellent yields (Table
2, 3b-3i). Bulky alkyl substituted phenols such as 3 or 4-tert-
butyl phenols, relatively more difficult to reduce due to their
steric hindrance, reacted well to give 63% and 79% yields,
2 | J. Name., 2012, 00, 1-3
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respectively. The cis/trans ratio followed the trend of the steric N-cyclohexylpyrrolidine
COMMUNICATION
(
5)
were formed in reasonable
size of alkyl substituents on phenols. For example, as shown in amounts at onset of this transformation, decreased to
3d 3f and 3h, the cis/trans ratio changed from 1/4.9 to 1/16 relatively small amount at the end of the reaction. The
with the increase in the substituent size, suggesting observation indicated that the two redox-isomers: N-
,
a
thermodynamically controlled process in which the trans- phenylpyrroline (
isomer is more favourable with the increasing size of 4-alkyl
4) and N-cyclohexylpyrrolidine (5)
Table 3 Substrate scope of pyrrolidines/indolines[a]
substituent in the cyclic six-membered ring conformation.16
Phenols bearing both electron-withdrawing and electron-
donating substituents all worked well to give the
corresponding products in moderate to excellent yields, with
R2
OH
Pd/C (10 mol%)
H
N
NaBH4 (50 mol%)
+
N
R2
TfOH (25 mol%)
1,4-dioxane, 150 o
C
1a
6
electron-donating substituent giving
a
higher yield than
2
electron-withdrawing one (3m vs 3l). As expected, both ortho-
or para- methoxy phenols afforded the desired products
smoothly; however, with the meta-methoxy phenol, the Ar-
OMe bond was completely cleaved during the reaction to give
N-cyclohexyl pyrrole (3a) in 43% yield likely due to the facile β-
elimination of the 3-methoxycyclohexanone intermediate.7k
When 4-fluorophenol was used as substrate, the
defluorination product was obtained, which was consistent to
our previous reports.[7j] It was worth mentioning that the
trifluoromethyl (3n), an extra phenolic OH (3p) and a sterically
bulky amide (3q) were all tolerated in this transformation.
Moreover, bio-active phenol derivatives, such as Tyramine and
Tyrosine, were suitable substrates for this transformation (3r
and 3u). Besides, di-substituted phenols also reacted
efficiently to give the desired products in moderate yields (3s
and 3t). Importantly, carvacrol, a natural product from the
essential oil of Origanum vulgare, underwent this
transformation as well (3t).
N
N
N
N
6c, 66%
6b, 90%
(41%)[b]
3a, 43%
(proline as the substrate)
6a, 88%
CO2Me
N
N
N
N
O
O
6d, 75%
6e, 45%
6f, 8%
6g, 33%
N
N
O
CO2Me
6h, 74%
6i, 39%
[a] Reaction conditions: phenol (0.2 mmol, 1 equiv), pyrrolidines (0.28 mmol, 1.4
equiv) or indolines (0.48 mmol, 2.4 equiv), Pd/C (10 mol%), TfOH (25 mol%) in
1,4-dioxane (1 mL) were stirred at 150 oC under argon in 10-mL sealed tube for 12
h; isolated yields were given. [b] Indoline-2-carboxylic acid was used as substrate.
On the other hand, the substrate scope of
pyrrolines/indolines was investigated as summarized in Table
3. Indoline worked well to give the corresponding N-
could be potentially converted into the desired product N-
cyclohexylpyrrole (3a). To examine this possibility, the control
experiments were tested (Scheme 2, c and d). As expected,
cyclohexylindole
(6b) in 90% isolated yield. The alkyl
substituted pyrroline or indolines such as 2-methylpyrrolidine
and 2- or 3-methylindolines were all effective substrates,
affording the corresponding pyrrole and indole derivatives in
both
4 and 5 could be converted into 3a in 48% and 55% NMR
yields, respectively.
good to excellent yields
(6a, 6c, 6d), while the 7-
Based on the above results, a tentative mechanism for this
formal aromaticity transfer reaction is proposed in Scheme 3.
This reaction could be initiated by the NaBH4 reacted with
palladium catalyst to generate the HPdIIH species,7j, which
methylindoline gave the corresponding product in relatively
lower yield probably due to the steric hindrance of 7-Me group
(
6g). Interestingly, when proline or indoline-2-carboxylic acid
15
were used as substrates, the corresponding decarboxylation
products were generated in moderate yields;7l, 13 however, the
corresponding methyl esters of proline and indoline-2-
carboxylic failed to give the products. The indoline-3-carboxylic
methyl ester gave a low yield while indoline-3-ethyl acetate
would reduce phenol (3a) to form the cyclohexanone or
cyclohexenone (I). Then, intermediate I could undergo fast
condensation with pyrroline (2a), catalyzed by TfOH, to give
the key intermediate II. If intermediate II went through 1,3-
hydride transfer to give intermediate III 14
,
intermediate IV
could afford the product in moderate yield (6f
with electron-donating substituent worked better than
electron-withdrawing one 6h 6i), in line with the
, 6e). Indoline
could be generated after deprotonation
.
Next, the desired
product (3a) could be obtained by dehydrogenation of
(
,
intermediate IV catalyzed by palladium to regenerate the
HPdIIH species,7j,15 as stated in Pathway A. Alternatively, based
on our previous work (Scheme 1, b and c),7k, 7j intermediate II
nucleophilicities of the indoline derivatives.
To investigate the possible mechanism, cyclohexanone and
cyclohexenone (the two possible reduced forms of phenol)
were used (Scheme 2, a and b). Both compounds could afford
the desired product in 62% and 47% NMR yields, respectively.
To further understand the mechanism, the kinetic profile of
this transformation was studied in Figure 1 (see SI for details).
The desired product 1a increased as the reaction proceeded.
could also be transformed to intermediates
the results of control experiments (Scheme 2), intermediates
and could both afford the desired product 3a by either
hydrogenation process Pathway or dehydrogenation
process (Pathway C) catalyzed by palladium.
4 or 5. Based on
4
5
(
B)
Interestingly, the two by-products N-phenylpyrrolidine (4) and
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Conclusions
In conclusion, we have developed a formal aromaticity-
transfer reaction between phenols and pyrrolines/indolines,
featuring atom- and redox-economies. A wide range of N-
cyclohexylpyrroles and N-cyclohexylindoles bearing various
functional groups were obtained by this novel method, starting
from the naturally abundant and sustainable phenols. Several
bio-active phenols such as Tyramine, Tyrosine and Carvacrol
are all suitable substrates in this transformation. Ongoing
studies regarding the synthetic applications of such
transformations are currently underway in our laboratory.
Acknowledgements
We are grateful to the Canada Research Chair Foundation (to
C.-J. Li), the CFI, FQRNT Center for Green Chemistry and
Catalysis, NSERC, McGill University for supporting our
research.
Scheme 2. Control experiments.
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13 For selected proline decarboxylation-coupling examples, see:
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14 For selected 1,3-hydride transfer examples, see: a) S. C. Pan,
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15 J. Zhang, Q. Jiang, D. Yang, X. Zhao, Y. Dong, R. Liu, Chem. Sci.
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16 For the 4-alkyl substitued cyclohexyl-1-H-Pyrrole:
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DOI: 10.1039/C7SC02578E
R2
Pd/C (10 mol%)
NaBH4 (50 mol%)
OH
H
N
N
+
H O
+
2
R1
TfOH (25 mol%)
1,4-dioxane, 150 oC
R1
R2
Formal aromaticity-transfer
Phenols as cyclohexyl synthons
Redox and atom efficiencies are presented
30 examples up to 94% yield
A formal “aromaticity-transfer” reaction between phenols and pyrrolines/indolines has been developed: a redox- and
atom-efficient method to synthesize N-cyclohexylpyrroles/indoles.