Highly atroposelective synthesis of arylpyrroles by catalytic asymmetric Paal-Knorr reaction

Article abstract of DOI:10.1021/jacs.6b09634

A general and efficient method for accessing enantiomerically pure arylpyrroles by utilizing the catalytic asymmetric Paal-Knorr reaction has been developed for the first time. A wide range of axially chiral arylpyrroles were obtained in high yields with

Full text of DOI:10.1021/jacs.6b09634

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Communication
Highly Atroposelective Synthesis of Arylpyrroles
by Catalytic Asymmetric Paal-Knorr Reaction
Lei Zhang, Jian Zhang, Ji Ma, Dao-Juan Cheng, and Bin Tan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Jan 2017
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Highly Atroposelective Synthesis of Arylpyrroles by Catalytic
Asymmetric Paal-Knorr Reaction
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Lei Zhang,†‡ Jian Zhang,† Ji Ma,† DaoꢀJuan Cheng,† and Bin Tan*†
†Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, China
‡Key Laboratory of Biomedical Polymers of Ministry of Education, College of Chemistry and Molecular Science, Wuhan
University, Wuhan, 430072, China
Supporting Information Placeholder
ABSTRACT: A general and efficient method for accessing
enantiomerically pure arylpyrroles by utilizing the catalytic
Axially chiral biaryl compounds are prevalent in biologically
active compounds, natural products as well as materials, and also
asymmetric PaalꢀKnorr reaction has been developed for the first
play a significant role in acting as chiral ligands or organocataꢀ
lysts.4 Owing to the importance of this structural motif, the cataꢀ
time. A wide range of axially chiral arylpyrroles were obtained in
high yields with good to excellent enantioselectivities. The key to
lytic atroposelective construction of biaryl scaffolds has been
success is the use of the combinedꢀacid catalytic system involving
intensively investigated and great progress has been accomplished
in recent years.4,5 In sharp contrast, the asymmetric synthesis of
a Lewis acid and a chiral phosphoric acid for achieving effective
enantiocontrol. Noteworthy is that an unexpected solventꢀ
axially chiral arylpyrroles remains largely unexplored, although it
exists in natural products (Marinopyrrole, MurrastifolineꢀF),6 antiꢀ
dependent inversion of the enantioselectivity was observed in the
HIV inhibitor (PBO)7 and recently as chiral ligands8 for asymmetꢀ
aboveꢀmentioned asymmetric reaction.
ric addition reactions (Scheme 2). However, the effective syntheꢀ
sis of optically pure arylpyrroles relies on conventional resoluꢀ
tion,9 which requires the stoichiometric amounts of chiral reaꢀ
As one of the most prominent classes of heterocyclic comꢀ
gents. Therefore, the development of a catalytic asymmetric synꢀ
pounds, pyrroles are key structural motifs in biologically active
thesis of axially chiral arylpyrroles is very challenging and highly
compounds and useful building blocks in the synthesis of natural
appealing.
products, as well as in material sciences.1,2 Accordingly, their
Scheme 2. The Biologically Active Compounds and Ligand
with Arylpyrrole Skeleton
synthesis has always been among the most important research
areas in synthetic chemistry and numerous methods have been
widely developed.2 One of the most common approaches for the
construction of pyrroles is the PaalꢀKnorr reaction in which 1,4ꢀ
diketones are converted into pyrroles from the reaction with priꢀ
mary amine or ammonia by acidꢀmediated dehydrative cyclizaꢀ
tion.3 Remarkably, this reaction was first reported in 1884
(Scheme 1a), however, catalytic asymmetric PaalꢀKnorr pyrrole
synthesis still remained elusive to date. One of the easily missing
reasons is the absence of intrinsic chirality at the pyrrole, revealꢀ
ing no obvious handle for asymmetric induction. We questioned
whether the formation of chiral pyrroles in the course of the reacꢀ
tion would be feasible. Here we report an acidꢀcatalyzed asymꢀ
metric PaalꢀKnorr reaction for atroposelective synthesis of axially
chiral arylpyrroles (Scheme 1b).
Cl
O
N
OH
Ph
N
N
Cl
O
N
N
OMe
Me
OH
O
OH
O
F3C
Cl
Ph
N
NH
H
Cl
anti-HIV inhibitor
amino alcohol
Chiral ligand
OMe
Murrastifoline-F
Marinopyrrole
PBO
To address this issue, we envisioned that chiral phosphoric acꢀ
ids (CPA),10 which have emerged as powerful organocatalysts for
various reactions within the past twelve years, may be capable of
facilitating this transformation enantioselectively by accelerating
the intramolecular nucleophilic addition to form hemiaminal on
the basis of previous mechanistic investigation on PaalꢀKnorr
reaction. Motivated by the previous elegant work involving
asymmetric Fischer indolization,11 and as part of our ongoing
interest in asymmetric construction of axially chiral compounds12
and phosphoric acid catalysis,13 we describe herein the results of
the investigation, leading to the first phosphoric acidꢀcatalyzed
atroposelective synthesis of axially chiral arylpyrroles via asymꢀ
metric PaalꢀKnorr pyrrole synthesis.
Scheme 1. Paal-Knorr Reaction for Pyrrole Synthesis
To validate the feasibility of the hypothesis, we initially conꢀ
ducted the PaalꢀKnorr reaction of 1,4ꢀdione 1a with 2ꢀ(tertꢀ
butyl)aniline 2a in CCl4 at room temperature in the presence of 10
mol% of spinolꢀderived phosphoric acid14 (R)ꢀC1 (Table 1, entry
1). Encouragingly, despite its high steric hindrance, the reaction
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16d
17e
18e
(S)ꢀC3
(S)ꢀC3
(S)ꢀC3
0
0
0
CCl4
CCl4
-
84
85
95
78
88
96
proceeded smoothly to give the axially chiral arylpyrrole 3aa in
94% yield with 68% ee. This proofꢀof principle result obviously
indicates that the control of axial chirality of arylpyrroles by using
the chiral phosphoric acidꢀcatalyzed asymmetric PaalꢀKnorr pyrꢀ
role synthesis was feasible. Having thus proven the efficiency of
the chiral phosphoric acid in the current system, we next turned
our attention to investigate the substituent effects and the axially
chiral backbone on the catalysts (Table 1, entries 2ꢀ10). As shown
in Table 1, the electron property and steric bulk on the aromatic
ring, as well as backbone have very strong influences on enantiꢀ
oselectivity. We were glad to find catalyst (S)ꢀC3 gave the best
result in terms of the enantioselectivity (72% ee) (Table 1, entry
3). The remarkable solvent effects were observed in this transforꢀ
mation (Table 1, entries 11ꢀ14 and Table S1 in Supporting Inforꢀ
mation (SI)). It is noteworthy that the absolute configuration of
the obtained product was reversed by only changing the solvent
from CCl4 to methanol (entry 14). The enantioselectivity was also
affected by the reaction temperature and reagents (Table 1, entries
15ꢀ16 and Table S1 in SI). Inspired by Yamamoto’s combinedꢀ
acid catalysis principle15 and Luo’s binaryꢀacid catalysis,16 in
which the phosphoric acid could be activated by a Lewis acid to
promote many challenging transformations, we imagined that the
combinedꢀacid system may prove a good opportunity to improve
the enantioselectivity of the model reaction via synergistic interꢀ
action between the substrates and the catalysts. Therefore, we
further optimized the reaction conditions by adding Lewis acids to
the reaction system. To our delight, 10 mol% of Fe(OTf)3 proꢀ
moted the reactions very well and the enantioselectivity was imꢀ
proved to 88% ee (Table 1, entries 17ꢀ18 and Table S2 in SI).
Finally, we identified the following protocol as optimal: When 1a
was treated with 2a in the presence of catalyst (S)-C3 (10 mol%)
and Fe(OTf)3 (10 mol%) in the mixture of CCl4 (0.3 mL) and
1
2
3
4
5
6
7
8
f
a
Unless otherwise stated, all reactions were carried out with 1a (0.15
b
mmol), 2a (0.1 mmol), CPA (0.01 mmol) in CCl4 (1 mL) at rt or 0 °C.
Isolated yield. c Determined by chiral HPLC analysis. d MgSO4 (100 mg)
was added. e MgSO4 (100 mg) and Fe(OTf)3 (10 mol%) were added.
f
CCl4/cyclohexane (0.3 mL/1.2 mL) as solvents.
With the optimized conditions in hand, we next examined the
substrate scope of various substituted 1,4ꢀdiketones. As shown in
Table 2, different substituents and substitution patterns on the
aromatic ring of the substrates (1aꢀ1m) were all tolerated to give
the corresponding products 3aa-3am in 85ꢀ95% yields with 86ꢀ
97% ee. Moreover, the substituted phenyl group could be replaced
with naphthyl (1n) or heteroaryl (1o) group without obviously
affecting the reaction results (3an and 3ao). Encouraged by these
results, we expanded the generality of the reaction with regard to
variation of ester functional groups. The desired products (Table
2, 3ap-3as) were formed with good axial chirality control and the
transformation proceeded almost equally well with different
groups, demonstrating the broad generality of this approach for
the synthesis of axially chiral arylpyrrole derivatives.
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Table 2. The Substrate Scope with Respect to 1,4-Diketonesa
R
C3
(S)-
(10 mol%)
NH2
R
O
Fe(OTf)3 (10 mol%)
t-Bu
Ar
N
+
Ar
CCl4/cyclohexane
t-Bu
O
MgSO4,
0
C
1a-1s
2a
3aa-3as
CO2Me
3aa
3-Br
, 4.0 d, 95%, 96%ee
, R =
3af
4-Cl
R =
,
,
4.0 d, 94%, 92%ee
4.0 d, 94%, 96%ee
4.0 d, 85%, 94%ee
4.0 d, 93%, 90%ee
,
4.0 d, 91%, 86%ee
3ab, R = 4-Br, 5.0 d, 90%, 92%ee
3ac, R = 3-F, 3.5 d, 91%, 95%ee
3ag
, R =
3-CF
,
3
N
3ah, R = 4-CF3,
o
t-Bu
R
3ai
,
3-H
,
3ad
4-F
R =
R =
, R =
, 5.0 d, 86%, 90%ee
cyclohexane (1.2 mL) at 0 C for 4 days, the axially chiral 3aa
was obtained in 95% isolated yield with 96% ee (Table 1, entry
18).
3aj
4-Me
3ae, R = 3-Cl, 4.0 d, 93%, 95%ee
3aa-3aj
CO2Me
CO2Me
CO2Me
CO2Me
Cl
Cl
F
F3C
F
Table 1. Optimization of the Reaction Conditionsa
N
N
N
N
t-Bu
t-Bu
t-Bu
t-Bu
Cl
3ak, 4.0 d,
94%, 94% ee
3al, 4.0 d,
92%, 95% ee
3am, 3.5 d,
93%, 97% ee
3an, 4.5 d,
86%, 86% ee
CO2Me
CO2Et
CO2iPr
CO2allyl
CO2Bn
N
N
N
N
N
S
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Br
Br
Br
3ar, 4.0 d,
Br
3as, 4.0 d,
3ao, 4.5 d,
93%, 86% ee
3ap, 4.0 d,
3aq, 4.0 d,
92%, 96% ee
94%, 96% ee
90%, 95% ee
91%, 94% ee
a All reactions were carried out with 1 (0.3 mmol), 2a (0.2 mmol), MgSO4
(200 mg), (S)ꢀC3 (0.02 mmol) and Fe(OTf)3 (0.02 mmol) in
CCl4/cyclohexane (0.6 mL/2.4 mL) at 0 °C.
entry catalyst T (ºC)
solvent
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
DCM
toluene
yield (%)b ee (%)c
To further explore the generality of this transformation, we
then evaluated the use of various aromatic amines (2a-2l). Most
reactions reached completion within 4 days and gave axially
chiral arylpyrroles (Table 3, 3aaꢀ3la) in high yields (83ꢀ95%)
with good enantioselectivities (85ꢀ98% ee). The electronic and
position properties of the aromatic ring substituents did not have
significant effects on the enantioselectivity of the asymmetric
PaalꢀKnorr reactions. It is noteworthy to point out that the ortho
group was not only restricted to tertꢀbutyl group, and the bromo,
iodo or phenyl group at this position could also be tolerant to give
the expected products with good to excellent enantiocontrol (3gaꢀ
3la). The absolute configuration of 3fa was determined as being
(aR) by Xꢀray diffraction analysis (See SI) and those of other
products were assigned by analogy.
1
(R)ꢀC1
(R)ꢀC2
(S)ꢀC3
(S)ꢀC4
(S)ꢀC5
(S)ꢀC6
(S)ꢀC7
(R)ꢀC8
(R)ꢀC9
(S)ꢀC10
(S)ꢀC3
(S)ꢀC3
(S)ꢀC3
(S)ꢀC3
(S)ꢀC3
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
94
90
94
91
93
92
90
92
91
92
71
89
ꢀ68
ꢀ13
72
70
66
53
14
<5
6
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ꢀ9
43
61
61
ꢀ52
75
cyclohexane 92
MeOH
CCl4
57
82
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dependent inversion of the enantioselectivity took place in all
Table 3. The Substrate Scope with Respect to Aromatic
Aminesa
1
2
3
4
reactions when treating several 1,4ꢀdiketones with 2ꢀ(tertꢀbutyl)
aniline 2a, albeit with relatively low ee values. Further investigaꢀ
tions are necessary to elucidate the solventꢀdependent results.19
CO2Me
O
CO2Me
O
(S)-C3 (10 mol%)
NH2
Fe(OTf)3 (10 mol%)
N
+
CCl4/cyclohexane
Table 4. The Generality of the Solvent-Dependencea,b,c
MgSO4,
0
C
Br
5
6
7
8
Br
2a-2l
N
1a
3aa-3la
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
9
t-Bu
t-Bu
t-Bu
t-Bu
Br
Br
Br
Br
10
11
12
13
14
15
16
17
18
19
20
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H
3aa
95%, 96% ee
I
Br
NO2
3da
83%, 98% ee
CO2Me
yieldb (%) eec (%)
(S)ꢀ3
entry
Ar
3ba
93%, 95% ee
3ca
95%, 94% ee
(S)ꢀ3aa
(S)ꢀ3ac
1
2
3
4
5
6
3ꢀBrꢀC6H4 (1a)
3ꢀFꢀC6H4 (1c)
3ꢀClꢀC6H4 (1e)
4ꢀClꢀC6H4 (1f)
2ꢀnaphthyl (1n)
2ꢀthienyl (1o)
83
82
83
80
77
83
ꢀ75
ꢀ76
ꢀ76
ꢀ73
ꢀ73
ꢀ74
CO2Me
CO2Me
CO2Me
N
N
N
N
(S)ꢀ3ae
t
-Bu
t-Bu
Br
Ph
Br
Br
Br
Br
(S)ꢀ3af
(S)ꢀ3an
(S)ꢀ3ao
Ph
Me
Me
3ga
94%, 85% ee
3ha
86%, 88% ee
3ea
95%, 96% ee
3fa
Ph
86%, 93% ee
CO2Me
CO2Me
CO2Me
CO2Me
a All reactions were carried out with 1 (0.15 mmol), 2a (0.1 mmol), (S)ꢀC3
(0.01 mmol) and Fe(OTf)3 (0.01 mmol) in CCl4 /EtOH (0.5 mL/1.5 mL)
at rt. b Isolated yield. c Determined by chiral HPLC analysis.
N
N
N
N
Br
I
I
Ph
Br
Br
Cl
Br
MeO2C
Br
Me
3ia
93%, 86% ee
3ja
3ka
87%, 88% ee
3la
94%, 86% ee
To gain further insight into the reaction mechanism, we perꢀ
formed extensive control experiments for trapping the intermediꢀ
ate. Fortunately, the key intermediate B could be isolated and the
enamine structure was confirmed by the analysis of NMR and
HRMS (For details to the corresponding discussion of the detailed
mechanism, see SI). These observations suggested that the desired
pyrrole formation might involve an enamine intermediate B folꢀ
lowed by acidꢀcatalyzed dehydrative cyclization, which is not
completely in agreement with the widely accepted pathway20 of
the PaalꢀKnorr reaction (Scheme 4). Additionally, we found that
the ester group is essential for asymmetric induction (For details,
see SI). As such, we proposed that combined catalysts play an
important role in promoting the cyclization step and creating a
suitable chiral environment for stereoinduction.15,16
95%, 90% ee
a
Unless otherwise stated, all reactions were carried out with 1a (0.15
mmol), 2 (0.1 mmol), MgSO4 (100 mg), (S)ꢀC3 (0.01 mmol) and Fe(OTf)3
(0.01 mmol) in CCl4/cyclohexane (0.3 mL/1.2 mL) at 0 °C for 4 d.
To demonstrate the utility of this transformation, we carried
out a preparative scale synthesis of product 3aa (Scheme 3a). The
reaction performed efficiently and there was almost no change in
chemical yield (92%) and enantioselectivity (95% ee), thus
suggesting that largeꢀscale chemical production of axially chiral
arylpyrroles may be possible. Motivated by the wide application
of chiral monophosphorus ligand17 and phosphine organocatalyst
in asymmetric catalysis,18 we has attempted to synthesize the
axially chiral phosphine 3ma. To our delight, the expected
product was obtained with good enantioselectivity (88% ee),
albeit with a relatively low yield (Scheme 3b).
Scheme 4. Proposed Reaction Process
Scheme 3. Preparative Synthesis of 3aa and Synthesis of
Axially Chiral Phosphine 3ma
CO2Me
O
CO2Me
(S)-C3 (10 mol%)
NH2
Fe(OTf)3 (10 mol%)
t-Bu
N
+
(a)
CCl4/cyclohexane
O
t-Bu
MgSO4,
0 C
Br
Br
2a
1a
(3.2 mmol, 1.01 g)
3aa
92% yield, 95% ee
CO2Me
O
CO2Me
O
(S)-C3 (10 mol%)
NH2
Fe(OTf)3 (10 mol%)
PPh2
N
+
CCl4/cyclohexane
(b)
PPh2
Cl
MgSO4,
0 C, 5 d
In summary, we have developed a general and efficient
method for accessing enantiomerically pure arylpyrroles by
utilizing the first catalytic asymmetric PaalꢀKnorr reaction. A
wide range of axially chiral arylpyrroles were obtained in high
yields with good to excellent enantioselectivities. The combinedꢀ
acid catalytic system involving a Lewis acid and a chiral
phosphoric acid was the key point to improve the
enantioselectivity. Interestingly, an unexpected solventꢀdependent
inversion of the enantioselectivity was observed. We anticipate
that this strategy will be applied to natural product synthesis and
Br
Cl
Br
2m
1a
(0.1 mmol)
3ma
(0.12 mmol)
41% yield, 88% ee
Stimulated by the dramatic solvent effect as mentioned above,
we expected to get the opposite enantiomer with the same
configurational chiral catalyst by just changing the solvent
system.19 After further optimizing the reaction conditions (For
details, see Table S3 in SI), we established the acceptable reaction
condition for the generality investigation of the solventꢀ
dependence in this reaction. As shown in Table 4, the solventꢀ
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Chem. Soc. 2016, 138, 6956. (o) Wang, J.; Chen, M.ꢀW.; Ji, Y.; Hu, S.ꢀB.;
Zhou, Y.ꢀG. J. Am. Chem. Soc. 2016, 138, 10413. (p) Mori, K.; Itakura,
T.; Akiyama, T. Angew. Chem., Int. Ed. 2016, 55, 11642.
the axially chiral arylpyrroles will have potential application in
asymmetric catalysis.
1
2
3
4
5
6
7
8
9
(6) (a) Ito, C.; Wu, T.ꢀS.; Furukawa, H. Chem. Pharm. Bull. 1990, 38,
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Chem. Pharm. Bull. 1993, 41, 2096. (c) Bringmann, G.; Tasler, S.; Enꢀ
dress, H.; Kraus, J.; Messer, K.; Wohlfarth, M.; Lobin, W. J. Am. Chem.
Soc. 2001, 123, 2703. (d) Hughes, C. C.; PrietoꢀDavo, A.; Jensen, P. R.;
Fenical, W. Org. Lett. 2008, 10, 629.
(7) Campiani, G.; Morelli, E.; Fabbrini, M.; Nacci, V.; Greco, G.; Noꢀ
vellino, E.; Ramunno, A.; Maga, G.; Spadari, S.; Caliendo, G.; Bergamini,
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization of all new compounds,
Table S1, Table S2, Table S3. This information is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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(8) Faigl, F.; Erdélyi, Z.; Deák, S.; Nyerges, M.; Mátravölgyi, B. Tet-
rahedron Lett. 2014, 55, 6891.
(9) (a) Bock, L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53, 374. (b)
Faigl, F.; Mátravölgyi, B.; Holczbauer, T.; Czugler, M.; Madarász, J.
Tetrahedron: Asymmetry 2011, 22, 1879.
Corresponding Author
tanb@sustc.edu.cn
Notes
(10) For pioneering work on chiral phosphoric acid catalysis, see: (a)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. For typical reviews, see: (c) Akiyama, T. Chem. Rev. 2007,
107, 5744. (d) Terada, M. Chem. Commun. 2008, 4097. (e) Rueping, M.;
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(18) (a) Ye, L.ꢀW.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140.
(b) Marinetti, A.; Voituriez, A. Synlett 2010, 174. (c) Fan, Y. C.; Kwon,
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are thankful for the financial support from the National Natuꢀ
ral Science Foundation of China (Nos. 21572095, 21602097),
Shenzhen special funds for the development of biomedicine, inꢀ
ternet,
new
energy,
and
new
material
industries
(JCYJ20150430160022510). B.T. thanks the Thousand Young
Talents Program for financial support.
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9-anthryl
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NH2
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CPA (10 mol%)
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Catalytic asymmetric Paal-Knorr reaction
Atroposelective synthesis of arylpyrroles
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axially chiral
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