Rhodium-catalyzed conversion of furans to highly functionalized pyrroles

Article abstract of DOI:10.1021/ja401386z

The synthesis of highly functionalized pyrroles has been achieved by reaction of rhodium-stabilized imino-carbenes with furans. The reaction features an initial [3+2] annulation to form bicyclic hemiaminals, followed by ring opening to generate trisubstituted pyrroles.

Full text of DOI:10.1021/ja401386z

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Communication
Rhodium-Catalyzed Conversion of Furans to Highly Functionalized Pyrroles
Brendan T Parr, Samantha A Green, and Huw Madoc Lynn Davies
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401386z • Publication Date (Web): 11 Mar 2013
Downloaded from http://pubs.acs.org on March 12, 2013
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Rhodium-Catalyzed Conversion of Furans to Highly Function-
alized Pyrroles
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Brendan T. Parr, Samantha A. Green and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322
Supporting Information Placeholder
transformations that are inaccessible with the do-
nor/acceptor rhodium carbenes derived from diazo com-
pounds.7 Typically donor/acceptor rhodium carbenes
undergo facile cyclopropanation (eq 2).8 Therefore, we
became intrigued by an anomalous result reported by
Fokin on attempted cyclopropanation of p-
methoxystyrene, which formed a dihydropyrrole (eq
3).6b
ABSTRACT: The synthesis of highly functionalized pyr-
roles has been achieved by reaction of rhodium-
stabilized imino-carbenes with furans. The reaction fea-
tures an initial [3+2]-annulation to form bicyclic hemi-
aminals, followed by ring-opening to generate trisubsti-
tuted pyrroles.
Pyrroles are common structural motifs in pharmaceu-
tical agents and smart materials, and development of
new methods for their syntheses remains an active
field.1,2 Recent approaches include nitrone/cyclopropane
cycloaddition,2a 4π–electrocyclizations of azapentadi-
enyl cations,2b metallonitrene condensation with aryl
acetaldehydes,2c tandem photochemical decomposition
of α-diazo oximes/formal [3+2]-cycloaddition,2e and
sequential inter- and intramolecular Buchwald/Hartwig
aminations.2f In this communication, we describe a nov-
el approach for the synthesis of pyrroles by reaction of
N-sulfonyltriazoles with furans catalyzed by dirhodium
tetracarboxylates (eq 1). In concurrent but independent
studies, Sarpong and co-workers have developed a com-
plementary approach to pyrroles by means of intramo-
lecular reactions of N-sulfonyltriazoles with allenes.3
CO2Me
Ph
p-MeOC6H4
H
CO2Me
Ph
(2)
N2
p-MeOC6H4
Rh2(S-DOSP)4
82% yield
Tf
Tf
N
N
p-MeOC6H4
p-MeOC6H4
N
(3)
N
Rh2(S-NTTL)4
Ph
Ph
92% yield
The atypical reaction was observed when p-
methoxystyrene, an electron rich system, was used as the
rhodium carbene trapping agent. Thus, we considered
whether other distinct transformations could be achieved
from rhodium-catalyzed reactions of triazoles with elec-
tron rich heterocycles.9 We began the study by examin-
ing the rhodium acetate-catalyzed reaction of 2,5-
dimethylfuran (1) with N-sulfonyltriazole 2. We were
pleased to find that the reaction resulted in the unprece-
dented formation of pyrrole 3 in 41% yield.
O
R4
O
O
R4
O
S
S
Rh(II)
N
R1
O
R1
R2
N
+
(1)
N
O
N
R3
R3
SO2Et
R2
SO2Et
N
Rh2(OAc)4
1,2-DCE, 70 °C
41% yield
Me
N
O
Me
Me
N
+
(4)
O
N
Ph
Ph
Me
We have a long-standing interest in the chemistry of
rhodium-stabilized donor/acceptor carbenes.4 The stand-
ard method of generating these carbenes has been the
rhodium-catalyzed extrusion of nitrogen from diazo
compounds.4 Recently Gevorgyan5 and Fokin5c-d,6a have
developed an alternative entry into donor/acceptor car-
benes beginning with N-sulfonyl-1,2,3-triazoles. We
have begun exploring the possibility of using N-
sulfonyltriazoles to achieve novel rhodium carbene
1
2
3
The conversion of furans and triazoles into pyrroles,
containing components coming from both of the original
heterocycles, is a novel convergent transformation.
Thus, we decided to pursue the optimum conditions and
scope of this unusual synthetic sequence. The reaction
was found to be highly dependent on both the solvent
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Page 2 of 5
and the dirhodium catalyst, as shown in the optimization carbenes derived from diazo compounds, as they under-
1
2
3
4
5
6
7
8
studies described by Table 1. Initially a number of achi-
ral dirhodium tetracarboxylates were screened (entries 1-
6), of which Rh2(OOct)4 proved superior (entry 3, 56%
yield). Highly electron deficient catalysts, such as
Rh2(TFA)4 and Rh2(pfb)4, did not generate any of the
pyrrole and triazole 2 was recovered (entries 5 and 6). A
hydrocarbon solvent (entry 7) was substantially less ef-
fective than 1,2-dichloroethane (1,2-DCE). The use of
chloroform, which has been reported as the optimum
solvent for carbenoid transformations from triazoles,6a
provided poor yields of the desired product (entry 8,
29% yield). We also examined some of the most estab-
lished chiral catalysts because they often provide im-
go a tandem cyclopropanation/Cope rearrangement with
2,5-dimethylfuran.11
Table 2. N-sulfonyltriazole 4 variationsa
O
R2
O
O
R2
O
S
Rh2(S-DOSP)4
S
O
1,2-DCE, 70 °C
N
N
Me
Me
Me
+
N
O
N
9
R1
R1
Me
10
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1
4a-i
5a-i
SO2Et
N
SO2Et
N
SO2Et
N
Me
Me
O
Me
O
O
Me
proved yields of products over the standard achiral cata-
Me
Me
10
lysts.6d,
When Rh2(S-DOSP)4 was implemented, an
F3C
t-Bu
F
efficient synthesis of the pyrrole 3 was achieved in 77%
yield (entry 9). In contrast, neither of the other amino
acid-derived catalysts, Rh2(S-NTTL)4 and Rh2(S-
PTAD)4, proved as efficacious (entries 10 and 11).
5a
5b
74% yield
5c
76% yield
79% yield
Ms
N
Ts
N
Me
Me
Ts
N
Me
O
O
O
Me
Me
Me
Table 1. Optimization studies for the synthesis of 3a
F
F
5d
5e
5f
81% yield
98% yield
84% yield
SO2Et
SO2Et
N
Rh(II)
solvent, 70 °C
N
Me
O
Me
Me
Ts
N
Ts
N
N
+
O
Me
Me
Ts
N
N
Ph
Ph
Me
O
O
Me
1
2
3
O
Me
Me
yieldb
entry
Rh(II)-cat.
solvent
Me
Br
OMe
Rh2(OAc)4
Rh2(esp)2
Rh2(OOct)4
Rh2(OPiv)4
1
2
3
4
5
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
41
35
56
31
0c
5g
73% yield
5h
91% yield
5i
70% yield
a4 (0.50 mmol, 1.0 equiv), 1 (1.5 mmol, 3.0 equiv) and Rh2(S-
DOSP)4 (9 mg, 0.005 mmol, 0.01 equiv) combined in 1,2-DCE
(2.0 mL) and heated at 70 °C for 4–24 h until consumption of 4
was apparent by TLC. Yields are isolated yields of purified prod-
ucts.
Rh2(TFA)4
Rh2(pfb)4
6
1,2-DCE
PhCH3
CHCl3
0c
Rh2(OOct)4
Rh2(OOct)4
7
42
29
77
41
55
8
Rh2(S-DOSP)4
Rh2(S-NTTL)4
Rh2(S-PTAD)4
9
1,2-DCE
1,2-DCE
1,2-DCE
The reaction was then extended to a range of furan
derivatives (6) and the results are summarized in Table
3. Furan itself did not provide a clean transformation,
and ring-opened dienal-type products were evident from
NMR analysis of the reaction residue.11 2-Methylfuran
resulted in the formation of a single regioisomer of the
3,4-disubstituted furan 7a in moderate yield (41%). As
with 1, 2,5-diethylfuran was an excellent substrate for
the pyrrole synthesis, furnishing 7b in 99% yield. The
reactions with asymmetrically 2,5-disubstituted furans
generally proceeded in high yields (65-89%) but in
many instances, mixtures of regiosiomers were formed,
as seen with 7c-e and 7g. Notably, in the case of 2-
(triisopropyl)siloxymethyl-5-methylfuran, the pyrrole 7f
was formed in a highly regioselective manner. Presuma-
bly in this case, the combination of steric crowding and
electronic deactivation by the C2-substitent causes the
reaction to be highly regioselective.
10
11
a2 (0.25 mmol, 1.0 equiv), 1 (0.75 mmol, 3.0 equiv) and
Rh2(Lig)n (0.0025 mmol, 0.01 equiv) combined in solvent (1.0
mL) and heated at 70 °C for 4–12 h until consumption of 2 was
b
c
apparent by TLC. Isolated yields. N-Sulfonyltriazole was recov-
ered.
With the optimal conditions in hand, the scope of car-
bene architecture in the pyrrole synthesis was examined
(Table 2). Steric and electronic variations in the 4-aryl
moiety on the triazole 4 had minimal impact in the effi-
cacy of the reaction (compare 5a–c and 5e–h). A variety
of N-sulfonyl-protecting groups on the triazole were
compatible with pyrrole formation; however, the N-tosyl
group furnished the highest yields of 5 (compare 5c–e).
The alkenyl triazole 4i, was also an effective substrate,
generating the pyrrole 5i in 70% yield. This reactivity is
in marked contrast to that observed with rhodium vinyl-
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Table 3. Furan 6 variationsa
In summary, we have developed a highly effective
synthesis of trisubstituted pyrroles from the rhodium-
catalyzed reaction of furans with N-sulfonyl-1,2,3-
1
2
3
4
5
6
7
8
O
O
O
S
R
R
O
O
S
R
Rh2(S-DOSP)4
1,2-DCE, 70 °C
O
S
N
N
R1
R2
O
R1
R2
N
+
+
triazoles. The reaction features
a formal [3+2]-
N
O
O
N
Ph
Ph
cycloaddition across the furan C2–C3 π–bond, followed
by acid-catalyzed rupture of the transient hemiaminal
and termination of the cascade by concomitant elimina-
tion/aromatization to generate the pyrrole nucleus.
R2
R1
Ph
6a-h
1 or 4f
7a-g
8a-g
Ts
SO2Et
N
Ts
N
Ts
N
N
Et
Me
Me
O
O
O
O
9
ASSOCIATED CONTENT
Ph
Ph
Ph
Ph
Me
Et
c-Hex
Bn
10
11
12
13
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7a
7b
99% yield
7c
7d
Supporting Information.
Synthetic details and spectral data. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
41% yield
>10:1 ratio
67% yieldb
71% yieldb
2:1 ratio
3:1 ratio
Ts
N
Me
Me
O
Ts
N
Ts
Ph
N
AUTHOR INFORMATION
Me
Me
O
O
Me
TIPSO
Corresponding Author
Ph
Ph
Me
TIPSO
83% yield
7f
7e
7g
hmdavie@emory.edu
65% yieldb
89% yieldb
>10:1 ratio
2:1 ratio
2:1 ratio
Notes
a2 or 4f (0.50 mmol, 1.0 equiv), 6 (1.5 mmol, 3.0 equiv) and
Rh2(S-DOSP)4 (9 mg, 0.005 mmol, 0.01 equiv) combined in 1,2-
DCE (2.0 mL) and heated at 70 °C for 4–24 h until consumption
of 4 was apparent by TLC. Yields are isolated yields of purified
The authors declare no competing financial interest.
ACKNOWLEDGMENT
1
products. Ratios (7:8) determined by H NMR analysis of crude
This work was supported by the National Science Founda-
tion (CHE 1213246). During the course of these studies,
we became aware that Professor Richmond Sarpong’s
group was conducting complementary studies on the syn-
thesis of pyrroles from reactions of N-sulfonyltriazoles with
allenes. We thank Professor Sarpong for sharing the results
of his studies with us.
reaction residue. bCombined yield of two regioisomers 7 and 8.
A mechanistic rationale for the formation of the pyr-
roles is provided in Scheme 1. Heating the triazole 4f in
the presence of the dirhodium catalyst generates the
imino carbene-intermediate 9 via tandem triazole ring-
opening and nitrogen extrusion.6 The rhodium carbene 9
reacts with the furan at C-3 to generate the zwitterion
10,9,11 which then closes to the hemiaminal 11. Ring-
opening of 11 under mildly acidic conditions would
generate 12, which is configured to aromatize to the pyr-
role 13. The requirement of attack of the rhodium car-
bene at the C-3-position would explain why furan failed
to give a clean reaction and the yield with 2-methylfuran
was modest. Both of these substrates would tend to react
with carbenoids at C-2, and the resulting zwitterionic
intermediates tend to ring-open to dienones.9,11
ABBREVIATIONS
Rh2(esp)2,
Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-
benzenedipropionic
tetrakis(perfluorobutyrate);
acid)];
Rh2(pfb)4,
Rh2(S-DOSP)4,
Dirhodium(II)
Dirhodium(II)
tetrakis[1-[[4-dodecylphenyl]sulfonyl-(2S)-prolinate];
Rh2(S-
NTTL)4, Dirhodium(II) tetrakis[N-naphthoyl-(S)-tert-leucinate];
Rh2(S-PTAD)4,
Dirhodium
(II)
tetrakis[N-phthaloyl-(S)-
adamantylglycine]
REFERENCES
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Scheme 1. Plausible mechanism for pyrrole for-
mation
O
O
Me
Ph
RhLn
R
Ts
Me
N
R
Ts
N
Ts
N
RhLn
N
Ph
N
70 °C
Ph
RhLn
10
4f
9
Ts
Ts
N
Me
O
Ts
N
N
Me
Me
(2) For recent representative examples of pyrrole synthesis, see: (a)
Humenny, W. J.; Kyriacou, P.; Sapeta, K.; Karadeolian, A.; Kerr, M.
A. Angew. Chem., Int. Ed. 2012, 51, 11088. (b) Narayan, R.; Froeh-
lich, R.; Wuerthwein, E.-U. J. Org. Chem. 2012, 77, 1868. (c) Chen,
F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (d) Ryab-
chuk, P.; Rubina, M.; Xu, J.; Rubin, M. Org. Lett. 2012, 14, 1752. (e)
R
O
O
Ph
Ph
H
H
Ph
R
R
13
12
11
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(f) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012,
134, 20230.
Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52, 1507.
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1996, 37, 4133.
(9) Davies, H. M. L.; Hedley, S. J. Chem. Soc. Rev. 2007, 36, 1109.
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(12) Generation of the zwitterion by an initial cyclopropanation
followed by ring-opening is unlikely because furanocyclopropanes
generated from donor/acceptor rhodium carbenes tend to undergo a
second cyclopropanation or a Cope rearrangement (see ref. 9).
1
2
3
4
5
6
7
8
(3) Schultz, E. E.; Sarpong, R., J. Am. Chem. Soc. submitted.
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lective Synthesis (2011) (Eds. De Vries, J. G.; Molander, G. A.; Ev-
ans, A. P.), 3, 513.
(5) (a) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463. (b)
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vorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. (d)
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S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. J. Am. Chem. Soc. 2011,
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9
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SYNOPSIS TOC
1
O
R4
O
O
R4
O
S
N
2
3
S
Rh(II)
R1
O
R1
R2
N
+
N
O
N
4
5
6
7
8
9
R3
R3
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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