Synthesis of 2-Monosubstituted Pyrroles by Intramolecular Addition of Amines via Reductive Amination with Dibutyliodotin Hydride Complex (Bu 2SnIH-HMPA)

Article abstract of DOI:10.1055/s-2003-43371

Various 2-monosubstituted pyrroles were prepared in a one-pot procedure via the reductive amination of formyl groups of multifunctional substrates 1 by using Bu₂SnIH-HMPA system.

Full text of DOI:10.1055/s-2003-43371

LETTER
137
Synthesis of 2-Monosubstituted Pyrroles by Intramolecular Addition of
Amines via Reductive Amination with Dibutyliodotin Hydride Complex
(Bu2SnIH–HMPA)
S
ynthesi
k
s
of 2-Mono
u
y
atramolecular
Add
S
ition of Amine
h
s
ibata, Hirofumi Kato, Nobuaki Kanazawa, Makoto Yasuda, Akio Baba*
Department of Molecular Chemistry, Science and Technology Center of Molecules, Atoms and Ions Control, Graduate School of
Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68797387; E-mail: shibata@chem.eng.osaka-u.ac.jp
Received 22 October 2003
tive, Bu2SnClH–HMPA, gave no pyrrole 2a at all where
only 3a was obtained under the same conditions (entry 4).
Abstract: Various 2-monosubstituted pyrroles were prepared in a
one-pot procedure via the reductive amination of formyl groups of
multifunctional substrates 1 by using Bu2SnIH–HMPA system.
Various aromatic amines were applicable to give pyrroles
2b–d in one-pot procedures by the reductive amination of
1 using Bu2SnIH–HMPA system followed by heating at
80 °C (entries 5–7). In the case of 1b, pyrrole 2e was also
obtained (entry 8). Enal having aromatic ketone 1c was
also reactive to give the corresponding pyrroles 2f–h
where reductive amination was carried out at –40 °C
(entries 9–11).
Key words: pyrroles, reductive amination, tin hydride, complex
We have been developing the unique reactivities of the
halogen-substituted tin hydride systems such as Bu2SnIH
and Bu2SnClH–HMPA which promote effective reduc-
tion of imines.1 In particular, Bu2SnClH–HMPA affords
effective reductive amination to give a wide range of sec-
ondary and tertiary amines in one pot procedures.2 Pyr-
roles are important heterocycles broadly used in materials
science3 and found in naturally occurring and biologically
important molecules.4 Accordingly, substantial attention
has been paid to develop efficient methods for the synthe-
sis of pyrroles, most known methods are for forming 2,5-
di- or polysubstituted pyrroles. Convenient methods have
scarcely reported for the construction of 2-monosubstitut-
ed pyrrole ring.5 Herein we wish to report a novel, and ef-
ficient method for construction of 2-monosubstituted
pyrroles via the reductive amination by di-n-butyliodotin
hydride (Bu2SnIH)–HMPA system.
A plausible reaction course is indicated in Scheme 2. Ini-
tially, reductive amination occurs by mixing Bu2SnIH–
HMPA with starting substrate 1 and an aromatic amine
(Scheme 1).
R
CHO
Bu2SnIH-HMPA
R
ArNH2
+
N
Ar
2
O
1
Scheme 1
It is cleared that halogenotin hydride bears high imine-se-
lectivity because formyl and enone groups of 1 were not
reduced at all. In the next stage, the resulting tin-nitrogen
bond adds to the remaining ketone moiety in 1 by heating.
At the last stage, the elimination of tin hydroxide gives
pyrroles 2. The reaction was carried out in a one-pot pro-
cedure hence no intermediates were isolated. The substit-
uent and ligand in the tin complex play important roles for
the synthesis of pyrroles. Bu2SnIH–HMPA is a trigonal
bipyramidal structure in which iodine substituent occu-
pies apical position.8 The Sn-halogen bond is responsible
for high imine-selectivity, which promotes the formation
of an iminium ion (I). As a result, electrophilicity of imine
is increased.1,2 The activated imine thus formed would be
reduced more rapidly than any other functionalities such
as starting formyl and enone moieties. After the imine-
selective reduction, tin-nitrogen bond is formed. High
coordination of tin is important for the intramolecular
addition. Namely, in the pentavalent tin amide (II), the
tin-nitrogen bond occupying the apical position bears
adequate nucleophilicity to the remaining carbonyl
groups.9,10
As shown in Table 1, first, it was found that enal 1a in the
presence of iodotin hydride in THF at 0 °C for 2 hours un-
derwent reductive amination with p-chloroaniline to give
secondary amine 3a in 74% yield (entry 1).6,7 Although no
cyclization occurred, this result indicates that reductive
amination was carried out effectively without affecting
the remaining enone functionality in 1a. Chloro-substitu-
ent on nitrogen aromatic ring was not reduced. After the
reductive amination, heating the mixture at 80 °C for 2
hours afforded pyrrole 2a in 22% yield with 60% of 3a
(entry 2). In this case, 1,4-dioxane was used as a solvent
to heat the reaction mixture at 80 °C. Noteworthy is that
under the same conditions, pyrrole 2a was obtained in
81% yield in the presence of an equimolar amount of
HMPA (entry 3), in which non-cyclized product 3a was
not obtained at all. The iodo-substituent on the tin center
was essential for the cyclization because chlorotin deriva-
SYNLETT 2004, No. 1, pp 0137–0139
0
5.
0
1.
2
0
0
4
Advanced online publication: 4.12.2003
DOI: 10.1055/s-2003-43371; Art ID: U21803ST
© Georg Thieme Verlag Stuttgart · New York

138
I. Shibata et al.
LETTER
Table 1 One-Pot Synthesis of 2-Monosubtituted Pyrroles 2a
Ar
Ar
R
Sn
N
R
CHO
Tin Hydride
Conditions 1
R
N
H
N
+
ArNH2
R
O
O
Ar
Conditions 2
1
O
2
3
Entry
R
Ar
Tin hydride
Solvent
Conditions
1
Condtions
2
Product
[Yield (%)]
1
2
n-C8H17 (1a)
p-ClC6H4
Bu2SnIH
Bu2SnIH
THF
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
3a (74)
Dioxane
80 °C, 2 h
2a (22)
3a (60)
3
4
Bu2SnIH–HMPA
Bu2SnClH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Bu2SnIH–HMPA
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
–40 °C, 2 h
–40 °C, 2 h
–40 °C, 2 h
80 °C, 2 h
80 °C, 2 h
80 °C, 2 h
80 °C, 2 h
80 °C, 2 h
80 °C, 2 h
60 °C, 2 h
60 °C, 2 h
60 °C, 2 h
2a (81)
3a (98)
2b (54)
2c (60)
2d (66)
2e (60)
2f (46)
2g (41)
2h (49)
5
Ph
6
p-Tol
7
p-MeOC6H4
8
PhCH2CH2CH2 (1b) p-ClC6H4
9
Ph (1c)
p-ClC6H4
Ph
THF
10
11
THF
p-MeOC6H4
THF
a Compound 1 1 mmol, ArNH2 1 mmol, tin hydride 1 mmol, (HMPA 1 mmol), 1 1 mmol, solvent 1 mL.
In conclusion, various 2-monosubstituted pyrroles could
be prepared in a one-pot procedure by the imine-selective
reduction of in situ formed bifunctional substrates bearing
imine and enone functionalities.
Acknowledgment
This research has been carried out at the Strategic Research Base
‘Handai Frontier Research Center’ supported by the Japanese
Government’s Special Coordination Fund for Promoting Science
and Technology, and was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture.
R
Bu2SnIH-HMPA
R
CHO
ArNH2
+
N
O
2
1
Ar
–H2O
–SnOH
I
H
H
H
I
O
R
Bu
O
R
H
Sn
N
Ar
SnO
N
Ar
H
Bu
Bu
Bu
R
R
HMPA
H
Sn
NAr
I
Sn
N
H
H
∆
Bu
Bu
O
Ar
HMPA
HMPA
(II)
( I )
Scheme 2 A plausible reaction mechanism
Synlett 2004, No. 1, 137–139 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Monosubstituted Pyrroles by Intramolecular Addition of Amines
139
was heated to 80 ºC and stirred for 2 h. The reaction was
quenched with MeOH (0.5 mL), and the residue was
chromatographed on silica-gel column [FL100-DX (Fuji
silysia)]. Elution with hexane gave pyrrole 2a (0.234 g,
81%).
References
(1) Shibata, I.; Moriuchi-Kawakami, T.; Tanizawa, D.; Suwa,
T.; Sugiyama, E.; Matsuda, H.; Baba, A. J. Org. Chem.
1998, 63, 383.
(2) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synlett 2000,
556.
(3) For most recent work, see: Lee, C.-F.; Yang, L.-M.; Hwu,
T.-Y.; Feng, A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am. Chem.
Soc. 2000, 122, 4992; and references therein.
Spectral data of representative products are as follows.
Compound 2a. IR: 1596, 1496 cm–1. 1H NMR (CDCl3): d =
0.86 (t, J = 6.83 Hz, 3 H), 1.21–1.30 (m, 10 H), 1.44–1.55
(m, 2 H), 2.49 (t, J = 7.81 Hz, 2 H), 6.04–6.06 (m, 1 H), 6.21
(t, J = 2.93 Hz, 1 H), 6.67–6.69 (m, 1 H), 7.22 (d, J = 8.79
Hz, 2 H), 7.39 (d, J = 8.79 Hz, 2 H). 13C NMR (CDCl3): d =
14.08, 22.63, 26.65, 29.13, 29.27, 29.30, 31.57, 31.80,
107.10, 108.26, 121.30, 127.30, 129.18, 132.77, 134.21,
139.06. HRMS: calcd for C18H24NCl: 289.1597. Found:
289.1597.
(4) For a review see: (a) Gossauer, A. In Pyrrole, Houben–
Weyl, Methods in Organic Chemistry, Vol. E6a/1; Thieme:
Stuttgart, 1994, 556. (b) See also: Boger, D. L.; Boyce, C.
W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54. (c) Fürstner, A.; Weintritt, H. J. Am. Chem.
Soc. 1998, 120, 2817. (d) See further: Sayah, B.; Pelloux-
Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65, 2824. (e) Liu,
J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org.
Chem. 2000, 65, 3587.
(5) For formation of the 2-monosubstituted pyrrole ring from g-
keto aldehydes or related precursors, see: (a) Ref.4a (b) See
also: Gadzhily, R. A.; Fedoseev, V. M.; Dzhafarov, V. G.
Chem. Heterocycl. Compd. 1990, 26, 874. (c) Engel, N.;
Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 676.
(d) For syntheses of 2-monosubstituted pyrroles via
acylation-reduction or alkylation of pyrrole see, for
example: Garrido, D. O. A.; Buldain, G.; Frydman, B. J.
Org. Chem. 1984, 49, 2619. (e) Muchowski, J. M.; Solas, D.
R. J. Org. Chem. 1984, 49, 203. (f) See also: Kel’in, A. V.;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123,
2074.
Compound 2e. IR: 1496 cm–1. 1H NMR (CDCl3): d = 1.75–
1.87 (m, 2 H), 2.51–2.59 (m, 4 H), 6.06–6.09 (m, 1 H), 6.18–
6.21 (m, 1 H), 6.66–6.68 (m, 1 H), 7.05–7.35 (m, 9 H). 13
NMR (CDCl3): d = 26.09, 30.67, 35.29, 107.39, 108.32,
121.46, 125.71, 127.19, 128.25, 128.31, 129.20, 132.76,
133.49, 138.87, 141.86. HRMS: calcd for C19H18NCl:
295.1128. Found: 295.1125.
C
Compound 2f. IR: 1600, 1492 cm–1. 1H NMR (CDCl3): d =
6.35–6.38 (m, 1 H), 6.42–6.44 (m, 1 H), 6.90–6.91 (m, 1 H),
7.09 (d, J = 8.40 Hz, 2 H), 7.13–7.24 (m, 5 H), 7.28 (d,
J = 8.40 Hz, 2 H). 13C NMR (CDCl3): d = 109.60, 110.99,
124.16, 126.49, 126.76, 128.18, 128.32, 129.13, 132.19,
132.59, 133.79, 139.01. HRMS: calcd for C16H12NCl:
253.0658. Found: 253.0653.
(8) Kawakami, T.; Shibata, I.; Baba, A. J. Org. Chem. 1996, 61,
82.
(6) For preparation of 1, see: Kobayashi, Y.; Nakano, M.;
Kumar, G. B.; Kishihara, K. J. Org. Chem. 1998, 63, 7505.
(7) Typical Experimental Procedure (see Table 1, entry 3).
To a dry nitrogen-filled 10 mL round-bottomed flask
containing di-n-butyltin dihydride (Bu2SnH2, 0.166 g, 0.5
mmol) in 1,4-dioxane (1 mL) was added di-n-butyltin
diiodide (Bu2SnI2, 0.243 g, 0.5 mmol) and HMPA (0.180 g,
1 mmol) at r.t. After stirring at r.t. for 10 min, the resulting
solution of di-n-butyliodotin hydride (Bu2SnIH, 1 mmol)
was cooled to 0 °C. Carbonyl substrate(1a) (0.196 g, 1
mmol), and p-chloroaniline (0.128 g) were added
successively, and stirring was continued at 0 ºC for 2 h. The
IR absorption band of Sn-H (1850 cm–1) disappeared, which
indicated the formation of stannylamide (II). The mixture
(9) We have already reported the increase of nucleophilicity of
Sn-N bonds by pentacoordination, see: (a) Shibata, I.; Baba,
A.; Iwasaki, H.; Matsuda, H. J. Org. Chem. 1986, 51, 2177.
(b) Baba, A.; Kishiki, H.; Shibata, I.; Matsuda, H.
Organometallics 1984, 4, 1329. (c) Shibata, I.; Baba, A.;
Matsuda, H. J. Chem. Soc., Chem. Commun. 1986, 1703.
(d) Shibata, I.; Nakamura, K.; Baba, A.; Matsuda, H. Bull.
Chem. Soc. Jpn. 1989, 62, 853.
(10) It seems that chlorodibutyltin amide moiety (Bu2ClSnN-)
does not has enough nucleophilicity to cause cyclization
because of the electron withdrawing character of Cl-
substituent (entry 4).
Synlett 2004, No. 1, 137–139 © Thieme Stuttgart · New York