Cross metathesis of N-allylamines and α,β-unsaturated carbonyl compounds: A one-pot synthesis of substituted pyrroles

Article abstract of DOI:10.1055/s-0030-1259083

A tandem reaction involving cross metathesis followed by concomitant cyclisation has been developed for the synthesis of substituted pyrroles. Various protected electron-deficient N-allylamines reacted with α,β-unsaturated carbonyl compounds in the presen

Full text of DOI:10.1055/s-0030-1259083

124
LETTER
Cross Metathesis of N-Allylamines and a,b-Unsaturated Carbonyl
Compounds: A One-Pot Synthesis of Substituted Pyrroles
A
One-Pot
Syy
ed
rroles Shafi,a Mariusz Kędziorek,b Karol Grela*a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Fax +48(22)3432109; E-mail: klgrela@gmail.com
b
Received 9 October 2010
on the development of a novel and flexible approach to
these heteroaromatic compounds. Although many reports
are present in literature that describe the synthesis of pyr-
roles through RCM of diallyl amines,4 and by other meth-
Abstract: A tandem reaction involving cross metathesis followed
by concomitant cyclisation has been developed for the synthesis of
substituted pyrroles. Various protected electron-deficient N-allyl-
amines reacted with a,b-unsaturated carbonyl compounds in the
presence of Lewis acids under the cross metathesis conditions using ods,7,8 a novel and efficient synthetic method remains an
selected Ru olefin metathesis catalysts in order to form pyrroles.
attractive goal. As part of our ongoing project on the ap-
plications of cross metathesis in the synthesis of hetero-
cyclic compounds, we report herein a straightforward
method for the preparation of pyrroles using protected N-
allylamines and a,b-unsaturated carbonyl compounds un-
der cross metathesis conditions.6
Key words: ruthenium, catalysis, olefin metathesis, Lewis acids,
heterocycles
In recent years, olefin metathesis has been regarded as one
of the most important C=C bond-forming processes and
has been utilized extensively in total syntheses.1 The ad-
vent of well-defined catalyst systems (Figure 1) that com-
bine excellent activity and broad functional group
compatibility has been the major factor in popularizing
this reaction.2 The wealth of synthetic transformations
that can be accomplished is astonishing, and there are
countless applications of metathesis to form complex
molecules. One of the most powerful tactics for the syn-
thesis of carbocyclic and heterocyclic frameworks is ring-
closing metathesis (RCM). Recently RCM has attracted
some interest as a new tool for the synthesis of aromatic
compounds.3
Initial studies were focused on examining the feasibility
of applying CM to various N-protected allylamines that
could be used for the synthesis of some marine alkaloids.
We have successfully performed the cross metathesis be-
tween N-tosyl-allylamine and tert-butylacrylate to form
the expected product 3 (Scheme 1).9 To our surprise,
when the same reaction was performed with crotanalde-
hyde 4, pyrrole 5 was formed along with the de-allylated
product 6 and traces of ‘homodimerised’ product 7, in-
stead of the cross metathesis product. Intrigued by this un-
expected observation, we decided to study this reaction in
more detail. The CM reaction between N-tosyl allylamine
and crotonaldehyde was chosen as a model reaction, and
However, in the context of aromatic and heteroaromatic
ring formation, rationally designed RCM strategies have
only recently been highlighted in the literature.4 Indeed,
many early examples of the synthesis of aromatic com-
pounds by RCM were viewed as unwanted side reac-
tions.5 Olefin cross metathesis (CM), on the other hand,
has recently become recognised as a tool for the synthesis
of aromatic and heteroaromatic compounds. Very recent-
ly, Donohoe demonstrated the synthesis of heteroaromatic
compounds with respect to pyrroles and furanes using a
two-step strategy involving a combination of cross meta-
thesis followed by Lewis acid catalysed cyclization.6 Cat-
alytic olefin CM is a convenient route to functionalise
olefins from simple alkene precursors and has gained a lot
of interest due to its applications in the formation of ver-
satile synthetic intermediates.1d,e
L
Ru
P
L
Ru
P
Ph
Cl
Cl
Ph
Cl
Cl
3
3
Ind-I, Ind-II
Cl
Gru-I, Gru-II
L
L
Cl
Ru
Ru
Cl
O
Cl
O
Z
Gre-II, Z = NO2
N
Hov-I, Hov-II
P
N
I: L =
II: L =
3
As the pyrrole system is prevalent in natural and synthetic
biologically active compounds, we focussed our attention
(SIMes)
I-generation
II-generation
I
II
SYNLETT 2011, No. 1, pp 0124–0128
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259083; Art ID: G30810ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Selected ruthenium olefin metathesis pre-catalysts

LETTER
A One-Pot Synthesis of Substituted Pyrroles
125
O
Lewis acids to examine the validity of this assumption. In-
terestingly, the pyrrole moiety was formed in moderate to
high yields in the presence of various Lewis acids within
significantly shorter reaction times (Table 2).
O
O
2
TsHN
Gre-II or Hov-II,
CH2Cl2, 40 °C
O
3
Table 2 Screening of Lewis Acids for the Cross Metathesisa
TsHN
Hov-II, Lewis acid
+
1
TsHN
CHO
CHO
toluene, 80 °C
N
Ts
4
+
TsNH2
+
Gre-II or Hov-II,
CH2Cl2, 40 °C
N
Lewis acid
LiCl
Acid amount (mol%) Time (min) Yield (%)b
Ts
100
100
100
100
100
120
120
120
60
5c
5c
5
6
TsHN
AlCl3
NHTs
Ti(Oi-Pr)4
Zn(OTf)2
RuCl3·nH2O
20c
60
60
7
Scheme 1 Cross metathesis of N-tosyl allylamine 1
45
a series of Grubbs-type Ru catalysts (Figure 1) were test-
ed. This catalyst screening (Table 1) indicated that the
model reaction did not work at all when Gru-I and Gru-
II were employed at 40 °C in CH2Cl2; the de-allylated
product 6 was found to be the major product in this case.
When the reaction temperature was raised to 80 °C in tol-
uene, only 5% of the pyrrole was isolated. Among the cat-
alysts tested, the highly active carbene catalysts Gre-II
and Hov-II gave pyrrole 5 in 32 and 65% yields, respec-
tively. This transformation was repeated in different sol-
vents (dichloroethane and toluene) at higher temperatures
and with higher catalyst loading (20 mol%), however, the
efficiency of the reaction did not improve. Under these
conditions, the de-allylated product 6 was present in the
reaction mixtures in all cases, which is probably due to the
facile isomerization of allyl amine to enamines and co-
ordination between the nitrogen and ruthenium.
O
B
O
100
90
60
Cl
PhBCl2
100
100
50
90
30
30
30
30
70
93
93
92
92
B(OPh)3
B(OPh)3
B(OPh)3
B(OPh)3
20
10
a Reaction conditions: N-tosyl allylamine (0.47 mmol), crotonalde-
hyde (2.3 mmol), Lewis acid, Hov-II (5 mol%), toluene (5 mL).
b Isolated yields.
c Catalyst decomposed.
This study indicated that B(OPh)3 is the best choice for
this reaction. When the CM was run in the presence of one
equivalent of B(OPh)3, the reaction gave the pyrrole in
93% isolated yield in 30 minutes. Decreasing the amount
of B(OPh)3 did not affect the yield significantly. Even
with a catalytic (10 mol%) amount of B(OPh)3, the reac-
tion afforded 5 in 92% yield within 30 minutes. AlCl3,
LiCl and Ti(OiPr)4 were too aggressive under these condi-
tions, and they resulted in decomposition of the catalyst
within a short time. From the above optimization trials,
Hov-II and triphenyl borate were selected for further in-
vestigation. This new protocol was then successfully used
in the synthesis of a set of substituted pyrrole derivatives
from protected N-allylamines (Table 3).
It is known that Lewis acids can be used in such difficult
cases to weaken the N···Ru coordination and inhibit the
C–C double bond isomerisation.9a Therefore, the same
model reaction was performed in the presence of various
Table 1 Catalyst Screening for Cross Metathesis
catalyst
+
CHO
TsHN
N
Ts
Catalyst
Catalyst (mol%) Time (h)
Isolated yield (%)
a
CH2Cl2
Tolueneb
Gru-I
Gru-II
Ind-I
10
10
10
10
5
48
48
48
48
36
36
–
5
8
The serendipitous formation of the pyrrole ring systems
can be explained by the plausible mechanism shown in
Scheme 2.6 The cross metathesis takes place first, which
leads in the formation of a,b-unsaturated carbonyl com-
pound 8, which (as the Z-isomer) undergoes immediate
cyclization10 and dehydration to form the pyrrole. The
isomerisation/cyclisation step proceeds faster in the pres-
ence of Lewis acids. This proposal was further confirmed
by a separate experiment, in which the CM reaction be-
tween 1 and acrolein diethyl acetal 9 was assessed
5
–
6
Ind-II
Gre-II
Hov-II
–
16
35
60
32
60
5
a Reaction temperature 40 °C.
b Reaction temperature 80 °C.
Synlett 2011, No. 1, 124–128 © Thieme Stuttgart · New York

126
S. Shafi et al.
LETTER
Table 3 Preperation of Substituted Pyrroles via CMa
Entry
1
N-Protected allylamine (X)
CM partner (Y)
Product (Z)
Time (min) Yield (%)b
30
30
30
92
90
60
NHTs
CHO
N
Ts
2
3
NHTs
NHTs
CHO
N
Ts
OEt
OEt
N
Ts
4
45
70
NHTs
CHO
N
Ts
5
6
45
45
60
54
NHTs
NHTs
N
O
O
Ts
N
Ts
O
7
60
30
NHTs
O
N
Ts
O
O
O
S
8
9
30
45
91
60
NH
S
OMe
MeO
N
CHO
CHO
O
O
NHBoc
N
Boc
H
N
10
11
75
75
60
60
N
N
H
CHO
CHO
N
H
O
O
Br
Br
Br
H
N
N
Br
Br
Br
Br
N
H
N
H
O
O
O
Br
Br
Br
12
90
43
H
N
N
CHO
N
H
N
H
O
H
N
N
13
14
50
90
57
N
CHO
CHO
N
Boc
Boc
O
O
O
O
H
15c
N
N
O
HN
O
NH
a Reagents and conditions: Hov-II (5 mol%), B(OPh)3 (10 mol%), 80 °C, toluene.
b Isolated yield.
c 1,2-Dichloroethane was used as solvent.
Synlett 2011, No. 1, 124–128 © Thieme Stuttgart · New York

LETTER
A One-Pot Synthesis of Substituted Pyrroles
127
R4
groups, such as N-benzyl, N-(1-methyl)benzyl, or N-
(2,4,6-trimethyl)phenyl, did not lead to a productive reac-
tion, probably due to the highly basic nature of the nitro-
gen atom. The same result (catalysts decomposition) was
observed, when unprotected allylamine was used as the
CM partner.
R2
O
catalyst
R1HN
+
R1HN
O
Lewis acid
toluene, 80 °C
R3
R4
R3
8
E-isomer
In conclusion, we have developed a new one-pot CM/
cyclization protocol for construction of the pyrrole ring
system, based on the reaction between electron-deficient
N-allylamines and a,b-unsaturated aldehydes and ke-
tones.11–13 We expect that this reaction can find applica-
tions in the synthesis of various pyrrole-containing
molecules.
R3
R3
R4
O
R3
R4
R1HN
– H2O
H
R4
N
R1
N
R1
OH
H
Z-isomer
Scheme 2 Plausible mechanism of pyrrole ring formation
Supporting Information for this article is available online at
(Scheme 3). This reaction gave a mixture of products, in-
cluding the expected cross metathesis product 10, alde-
hyde 11 and pyrrole 5 in a 30:7:1 ratio. Compound 11 was
difficult to isolate because it cyclised immediately.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank the ‘Kasa Mianowskiego’ Foundation and the
Foundation for Polish Science for the postdoctoral fellowship (for
S.S.) and for a professorship ‘Mistrz’ (for K.G.).
OEt
OEt
OEt
OEt
Hov-II (5 mol%)
CH2Cl2, 40 °C
+
TsHN
TsHN
9
1
10
References and Notes
(1) For reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem. Int. Ed. 2005, 44, 4490. (b) Handbook of
Metathesis, Vol. 1-3; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003, 1234. (c) Furstner, A. Angew. Chem. Int.
Ed. 2000, 39, 3012. (d) Blechert, S.; Connon, S. J. Angew.
Chem. Int. Ed. 2003, 42, 1900. (e) Vernall, A. J.; Abell,
A. D. Aldrichimica Acta 2003, 36, 93.
(2) (a) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H.
Angew. Chem. Int. Ed. 2002, 41, 4035. (b) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168. (c) Scholl, M.; Ding, S.; Choon, W.
L.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (d) Kingsbury,
J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 791. (e) Schwab, P.; France,
M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2039.
TsHN
CHO
+
+
N
Ts
11
5
Scheme 3 Cross metathesis between 1 and 9
When pure isolated compound 10 was reacted with p-tol-
uene sulfonic acid, compound 5 was formed within ten
minutes (Scheme 4). This suggests that the reaction in-
volved in pyrrole formation does indeed proceed through
a highly reactive cross metathesis product i.e., an a,b-un-
saturated carbonyl compound, which undergoes concom-
itant cyclisation to form the pyrrole under the reaction
conditions.
(3) (a) Michaut, A.; Rodriguez, J. Angew. Chem. Int. Ed. 2006,
45, 5740. (b) Martin, S. F.; Deiters, A. Chem. Rev. 2004,
104, 2199. (c) McReynolds, M. D.; Dougherty, J. M.;
Hanson, P. R. J. M. Chem. Rev. 2004, 104, 2239.
OEt
TsHN
PTSA
OEt
N
CH2Cl2, 25 °C
Ts
10
(d) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev.
2009, 109, 3743. (e) Donohoe, T. J.; Fishlock, L. P.;
Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716.
5
Scheme 4 Deprotection of isolated acetal 10 leading to 5
(4) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem. Int.
Ed. 2006, 45, 2664; and references cited therein.
To assess the generality of this reaction, cross metathesis
reactions between a range of substituted N-allylamines
and various a,b-unsaturated carbonyl compounds were
performed using 5 mol% Hov-II catalyst and 10 mol%
B(OPh)3 in toluene at 80 °C for 30–120 min; the results
are summarized in Table 3.
(5) (a) Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J. P.
A. Tetrahedron Lett. 1999, 40, 3247. (b) Kinderman, S. S.;
Doodeman, R.; van Beijma, J. W.; Russcher, J. C.; Tjen,
K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.;
van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.;
Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736.
(6) (a) During the preparation of this manuscript, a related two-
step approach to substituted pyrroles via olefin cross meta-
thesis and subsequent acid-catalysed cyclisation was
published by Donohoe et al., presenting also an excellent
example of the application of this methodology towards the
synthesis of the tetrasubstituted pyrrole subunit of
We also noted that when the protecting groups of the allyl-
amine partner were electron-withdrawing (Ts, Boc, etc.),
the pyrroles were formed in moderate to high yields.
However, allyl amines protected with electron-donating
Synlett 2011, No. 1, 124–128 © Thieme Stuttgart · New York

128
S. Shafi et al.
LETTER
Atorvastatin, see: Donohoe, T. J.; Race, N. J.; Bower, J. F.;
Callens, C. K. A. Org. Lett. 2010, 12, 4094. (b) Donohoe,
T. J.; Bower, J. F. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
3373. (c) Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 3279.
mL) and stirred for 5 min under an argon atmosphere. The
first portion of the catalyst Hov-II (10.5 mg, 2.5 mol%) was
added as a solid. The reaction mixture was heated to reflux
and, after 15 min, the second portion of the catalyst was
added (10.5 mg, 2.5 mol%) under an argon atmosphere and
heating was continued until the reaction was complete
according to TLC. The reaction mixture was cooled and the
solvent was evaporated. The crude product was purified by
flash chromatography (c-hexane–EtOAc, 19:1) to yield 10z
as a colourless solid (64.01 mg, 60%); Mp 56–58 °C. 1H
NMR (500 MHz, CDCl3): d = 6.36 (t, J = 2.30, 2.29 Hz,
2 H), 6.37–6.38 (m, 1 H), 6.98–6.99 (m, 1 H), 7.11–7.14 (m,
(7) Poulard, C.; Cornet, J.; Legoupy, S.; Dujardin, G.; Dhal, R.;
Huet, F. Lett. Org. Chem. 2009, 6, 359.
(8) Saito, A.; Konishi, T.; Hanzawa, Y. Org. Lett. 2010, 12, 372;
and references cited therein.
(9) For selected examples of CM with allyl amines, see:
(a) Vedrenne, E.; Dupont, H.; Sabrina, O.; Elkaïm, L.;
Grimaud, L. Synlett 2005, 670. (b) Dewi, P.; Blechert, S.
Eur. J. Org. Chem. 2006, 1852. (c) Gebauer, J.; Dewi, P.;
Blechert, S. Tetrahedron Lett. 2005, 46, 43. (d) Chatterjee,
A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
1 H), 7.52 (t, J = 2.29, 2.30 Hz, 2 H), 9.86 (br, 1 H). 13
NMR (125 MHz, CDCl3): d = 111.19, 112.71, 117.61,
C
120.65, 123.92, 124.95, 159.01. IR (KBr): 3306, 3158, 2958,
2924, 1645, 1545, 1467, 1456, 1424, 1412, 1389, 1345,
1277, 1244, 1138, 1108, 1099, 1074, 1042, 990, 941, 887,
864, 842, 766, 751, 728, 630, 604 cm–1. MS (EI): m/z (%) =
160 (91) [M]+·, 94 (100), 67 (48), 66 (28). HRMS (EI): m/z
calcd for C9H8N2O: 160.06366; found: 160.06381. Anal.
Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49. Found: C,
67.44; H, 4.88; N, 17.57.
(10) Paulus, O.; Alcaraz, G.; Vaultier, M. Eur. J. Org. Chem.
2002, 14, 2565.
(11) General procedure: All reactions were performed using
Schlenk techniques under an argon atmosphere. Solvents
were degassed (using Freeze–Pump–Thaw techniques)
before use. Metathesis catalysts and all commercially
available chemicals were used as received. See the
Supporting Information for full experimental procedures
and product characterisation data
(12) Pyrrol-1-yl(1H-pyrrol-2-yl)methanone (10z); Typical
procedure: In a dry Schlenk tube, substrate 10x (100 mg,
0.66 mmol), B(OPh)3 (19 mg, 10 mol%) and crotonaldehyde
(233 mg, 3.3 mmol) were dissolved in anhydrous toluene (5
(13) This work was presented for the first time during the
European Congress of Young Chemists ‘YoungChem
2009’, Warsaw, Poland, October 14–18, 2009: ‘Ru catalyzed
imine formation followed by RCM of N- allylamines: A
tandem reaction towards the synthesis of substituted
pyrroles’; S. Shafi, oral presentation
Synlett 2011, No. 1, 124–128 © Thieme Stuttgart · New York

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