Synthesis of 4-aryl-2,3-dihydropyrroles via Rh-catalyzed intramolecular hydroamino-methylation reaction

Article abstract of DOI:10.1016/j.tetlet.2014.06.011

The rhodium-catalyzed intramolecular hydroaminomethylation reaction, generating 4-aryl-2,3-dihydropyrroles, has been developed. Triphenylphosphine has been proved to be the excellent ligand to prepare the dihydropyrrole derivatives in up to 99% yield. Thi

Full text of DOI:10.1016/j.tetlet.2014.06.011

Tetrahedron Letters 55 (2014) 4489–4491
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Tetrahedron Letters
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Synthesis of 4-aryl-2,3-dihydropyrroles via Rh-catalyzed
intramolecular hydroamino-methylation reaction
⇑
Xin Zheng , Bonan Cao , Xumu Zhang
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The rhodium-catalyzed intramolecular hydroaminomethylation reaction, generating 4-aryl-2,3-dihydro-
pyrroles, has been developed. Triphenylphosphine has been proved to be the excellent ligand to prepare
the dihydropyrrole derivatives in up to 99% yield. This procedure provides an efficient and simple alter-
native route to synthesize 4-aryl-2,3-dihydropyrrole derivatives only in one step.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 May 2014
Revised 4 June 2014
Accepted 4 June 2014
Available online 12 June 2014
Keywords:
Hydroaminomethylation
Dihydropyrrole
Intramolecular
Rhodium
N-Heterocyclic moieties are universal skeletons in biologically
and physiologically active alkaloids1 (Fig. 1). 4-Aryl-2,3-dihydrro-
pyrrole derivatives are the key intermediates in the synthesis of
( )-Mesembrine,2 Elwesine,3 and other bioactive alkaloids
(Fig. 2). Numerous organic methodologies have been developed,
in the past decades, but none of them could establish 4-aryl-2,3-
dihydrropyrroles only in one step.4 Long reaction procedures with
low to modest yields limited the application of these valuable
building blocks in total synthesis.
Hydroaminomethylation is a one-pot tandem reaction, which is
a superior methodology over conventional ones from economical
and environmental aspects.5 It firstly generates aldehydes by
hydroformylation of alkenes, and then the aldehydes immediately
react with primary or secondary amines to provide intermediate
imines. The final step is hydrogenation of imine intermediates to
obtain the secondary or tertiary amines. Intramolecular hydroami-
nomethylation of substituted cinnamylamine is a remarkable
method to access dihydropyrrole derivatives only in one step.
Therefore, in this Letter, we report the rhodium-catalyzed intramo-
lecular hydroaminomethylation with excellent yields (up to 99%).
The hydroaminomethylation of (E)-N-benzylcinnamylamine 1a
was initially investigated as a model reaction catalyzed by rho-
dium complexes bearing representative bidentate or monodentate
phosphorous ligands. When 1a was catalyzed by Xantphos at 80 °C,
the expected product 2a was only yielded 1% (Table 1, entry 1).
Figure 1. Structures of biologically active alkaloids with pyrrolidine moieties.
⇑
Corresponding author. Tel.: +1 814 880 4373; fax: +1 732 445 6312.
E-mail address: xumu@rci.rutgers.edu (X. Zhang).
Figure 2. Transformation of 3-aryl dihydropyrrole into bioactive alkaloids.
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2014.06.011
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

4490
X. Zheng et al. / Tetrahedron Letters 55 (2014) 4489–4491
Table 1
Other two bidentate ligands Bisbi and dppb also displayed poor
reactivates (Table 1, entries 2 and 3). In order to improve the yield,
several monodentate phosphorous ligands were chosen for this
reaction. No desired product was detected when the reaction was
carried out with P(OPh)3 ligand. A remarkable improvement of
the yield to 83% was observed by employing PPh3 as ligand (Table 1,
entry 6). Further changing PPh3/Rh(acac)CO2 ratio (L/Rh) to either
15 or 5 cannot improve the reaction yield (Table 1, entries 7 and 8).
Solvent, as a crucial factor for hydroaminomethylation, was
next screened. The results are summarized in Table 2. Toluene
was finally chosen as the best solvent (Table 2, entry 1). On the
basis of these results, different H2/CO pressure ratios were tested.
When the total pressure increased to 30 bar, the yield was slightly
decreased to 81% (Table 2, entry 7). A similar result was obtained
when the total pressure decreased to 10 bar. Under 20 bar total
syngas pressure constantly, H2/CO ratio was varied to 1/2 and
the yield was comparable with H2/CO ratio 1/1 (Table 2, entry 8).
Increasing H2 partial pressure cannot further hydrogenate dihydro-
pyrrole to pyrrole, but dramatically dropped the yield to 68%
(Table 2, entry 9). Herein, the ratio was 1/1 in 20 bar was the best
syngas pressure for this reaction.
Rh-catalyzed hydroaminomethylation of 1a with different ligandsa
Entry
Ligand
L/Rh
Yieldb (%)
1
2
3
4
5
6
7
8
Xantphos
Bisbi
dppb
P(OPh)3
P(o-toyl)3
PPh3
10
10
10
10
10
10
5
1
57
3
NR
11
83
78
67
PPh3
PPh3
15
a
Reaction conditions: 1a (1 mmol), Rh(acac)CO2 (0.2 mol %), ligand (2 mol %),
total 0.5 mL in toluene at 80 °C for 8 h.
b
Isolated yield.
Table 2
Optimization of reaction conditionsa
Lowering temperature from 80 °C to 60 °C furnished 2a in 40%
yield (Table 2, entry 10). Surprisingly, decreasing Rh concentration
from 0.2 mol % to 0.1 mol % considerably increased the yield to 99%
(Table 2, entry 13). However, doubling the metal concentration led
to a drop of yield dramatically (Table 2, entry 14). Therefore, the
optimal reaction condition was carried out by rhodium complex
bearing PPh3 ligand (1 mol %) in toluene at 80 °C under
H2/CO = 10/10 bar.
Entry
Solvent
Temp (°C)
[Rh]
H2/CO (bar)
Yield (%)
With the optimized reaction conditions in hand, a series of 1a
derivatives was successfully converted to desired 4-aryl-2,3-dihy-
dropyrroles with moderate to excellent yields (Table 3). Most of
electron-withdrawing substituents at the phenyl ring of the cin-
namyl group could generate the final products with excellent
yields. The reaction also performed well when varying the amine
substituents with different alkyl groups (Table 3, entries 10–12).
Notably, the tetrahydropyridine skeleton could be synthesized in
excellent yield (90%) (Table 3, entry 15).
1
2
3
4
5
6
7
8
9
10
11
12
13b
14c
Toluene
EtOAc
Acetone
THF
80
80
80
80
80
80
80
80
80
60
80
80
80
80
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.002
0.001
0.004
20 (1/1)
20 (1/1)
20 (1/1)
20 (1/1)
20 (1/1)
10 (1/1)
30 (1/1)
20 (1/2)
20 (2/1)
20 (1/1)
20 (1/1)
20 (1/1)
20 (1/1)
20 (1/1)
83
71
60
60
5
76
81
82
68
40
83
83
99
68
DCM
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Conclusions
a
b
c
In summary, intramolecular hydroaminomethylation provides
an efficient alternative approach for the synthesis of 4-aryl-2,
Reaction conditions: 1a (1 mmol), PPh3 (2 mol %), total 0.5 mL for 8 h.
PPh3 1 mol %.
PPh3 4 mol %.
Table 3
Expanding the scope of substratesa
Entry
1
Substrate
Product
Entry
9
Substrate
Product
2
10

X. Zheng et al. / Tetrahedron Letters 55 (2014) 4489–4491
4491
Table 3 (continued)
Entry
Substrate
Product
Entry
11
Substrate
Product
3
4
5
12
13
6
14
15
7
8
a
Reaction conditions: 1 (1 mmol), Rh(acac)CO2 (0.1 mol %), PPh3 (1 mol %), CO/H2=10/10, total 0.5 mL in toluene at 80 °C for 8 h.
2. Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133, 10376–10378.
3. Matsumura, Y.; Terauchi, J.; Yamamoto, T.; Konno, T.; Shono, T. Tetrahedron
1993, 49, 8503–8512.
3-dihydropyrroles only in one step with mild reaction conditions
and up to 99% yield.
4. (a) Kwok, S. W.; Zhang, L.; Grimster, N. P.; Fokin, V. V. Angew. Chem., Int. Ed.
2014, 53, 3452–3456; (b) Schwalm, C. S.; Castro, I. B. D.; Ferrari, J.; Olivera, F. L.;
Aparicio, R.; Correia, C. R. D. Tetrahedron Lett. 2012, 53, 1660–1663; (c) Busacca,
C. A.; Dong, Y. Tetrahedron Lett. 1996, 37, 3947–3950; (d) Nairoukh, Z.; Blum, J. J.
Org. Chem. 2014, 79, 2397–2403; (e) Wu, L.; Fleischer, I.; Jackstell, R.; Beller, M. J.
Am. Chem. Soc. 2013, 135, 3989–3996.
Acknowledgements
This research was supported by the National Science Founda-
tion (NSF CHE 0956784).
5. Crozet, D.; Urrutigoity, M.; Kalck, P. ChemCatChem 2011, 3, 1102–1118.
References and notes
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