Three-component synthesis of N-boc-4-iodopyrroles and sequential one-pot alkynylation

Article abstract of DOI:10.1021/ol900581a

(Hetero)aryl-, alkenyl-, and selected alkyl-substituted acid chlorides can be efficiently coupled with N-Boc-protected propargylamine to produce ynones which are converted in a one-pot fashion to 2-substituted N-Boc-4-iodopyrroles. Upon addition of a furt

Full text of DOI:10.1021/ol900581a

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2269-2272
Three-Component Synthesis of
N-Boc-4-iodopyrroles and Sequential
One-Pot Alkynylation|
Eugen Merkul,† Christina Boersch,† Walter Frank,‡,§ and Thomas J. J. Mu¨ller*,†
Institut fu¨r Organische Chemie und Makromolekulare Chemie and Institut fu¨r
Anorganische Chemie und Strukturchemie, Heinrich-Heine-UniVersita¨t Du¨sseldorf,
UniVersita¨tsstrasse 1, D-40225 Du¨sseldorf, Germany
thomasjj.mueller@uni-duesseldorf.de
Received March 19, 2009
ABSTRACT
(Hetero)aryl-, alkenyl-, and selected alkyl-substituted acid chlorides can be efficiently coupled with N-Boc-protected propargylamine to produce
ynones which are converted in a one-pot fashion to 2-substituted N-Boc-4-iodopyrroles. Upon addition of a further alkyne, another Sonogashira
coupling can be carried out in a one-pot fashion. This sequentially Pd/Cu-catalyzed process represents a very mild and efficient entry to
2,4-disubstituted N-Boc-pyrroles.
Among five-membered heterocycles, pyrroles are the most
prominent ones1 since they constitute important classes of
natural products,2 synthetic pharmaceuticals,3 and electrically
conducting materials such as polypyrroles.4 Therefore, the
development of new pyrrole syntheses and synthetic strate-
gies has remained an ongoing challenge.5 In particular,
multicomponent approaches have inevitably become increas-
ingly important due to their elegance and practicability.6
Furthermore, the quest for mild synthetic methods for
compounds with unusual substitution patterns such as 2,4-
disubstituted pyrroles has turned out to be nontrivial.7 As
part of our program to develop multicomponent syntheses
| Dedicated to Prof. Dr. Matthias W. Haenel on the occasion of his 65th
birthday.
of heterocycles initiated by transition-metal catalysis,8
a
† Institut fu¨r Organische Chemie and Makromolekulare Chemie.
‡ Institut fu¨r Anorganische Chemie and Strukturchemie.
§ X-ray structure analysis.
strategy based upon alkynones via Sonogashira coupling9
becomes apparent. Here, we communicate a concise, one-
pot synthesis of Boc-protected 2-substituted 4-iodopyrroles
and first examples of sequentially Pd/Cu-catalyzed subse-
quent alkynylations, also in a one-pot fashion.
(1) For some recent reviews, see: (a) Fan, H.; Peng, J.; Hamann, M. T.;
Hu, J.-F. Chem. ReV. 2008, 108, 264. (b) Schmuck, C.; Rupprecht, D.
Synthesis 2007, 3095. (c) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-
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Fu¨rstner, A. Angew. Chem. Int. Ed. 2003, 42, 3582. (f) Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753.
In the past years, the Sonogashira coupling of acid
chlorides with terminal alkynes using only 1 equiv of
triethylamine has proven to be a very effective tool for the
formation of ynones,10 which can be further reacted with
various nucleophiles in a one-pot fashion,11 opening an entry
to many consecutive multicomponent syntheses of hetero-
(2) For excellent reviews, see, e.g.: (a) Gossauer, A. Die Chemie der
Pyrrole; Springer Verlag: Berlin, 1974. (b) Gossauer, A. In Houben-Weyl,
Methoden der Organischen Chemie; Kreher, R., Ed.; G. Thieme Verlag:
Stuttgart, 1994; Bd. E6a, p 556. (c) Sundberg, R. J. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon Press: Oxford, 1996; Vol. 2, p 119. (d) Fu¨rstner, A. Synlett
1999, 1523.
(3) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p 207.
(4) For an interesting review, see, e.g.: MacDiarmid, A. G. Synth. Met.
1997, 84, 27.
10.1021/ol900581a CCC: $40.75
Published on Web 05/08/2009
 2009 American Chemical Society

cycles.8,9 Most interestingly, the subsequent additions to
alkynones are restricted to not only Brønsted basic conditions
but also Brønsted acid mediated transformations for the one-
pot synthesis of halofurans,12 and oxazoles13 via the inter-
mediacy of propargyl ketone derivatives can be easily
realized as a consequence of the mild reaction conditions of
the Sonogashira coupling (Scheme 1).
nent access would be highly desirable. For the three-
component synthesis of the 4-iodopyrroles with a nitrogen
protecting group, propargyl amides appear to be the most
suitable starting materials. Since the cycloisomerization to
an oxazole under acidic conditions could jeopardize this
endeavor, the choice of the right nitrogen protecting group
plays a key role. The Boc group is a versatile carbamate
protecting group for the pyrrole nitrogen atom, useful for
many transformations on the pyrrole core and easily remov-
able. Therefore, upon reacting toluoyl chloride (1a) and
N-Boc-protected propargylamine (2) under modified Sono-
gashira conditions, the intermediate alkynone 3a16 was
obtained. Without isolation, the concluding addition-cyclo-
condensation furnishes the N-Boc-4-iodo-2-p-tolylpyrrole
(4a) (Scheme 2). The final addition-cyclocondensation step
Scheme 1. Switching Conditions from Brønsted Basic to Brønsted
Acidic Conditions Leading to Coupling-Addition-Cyclocondensation
and Coupling-Cycloisomerization Sequences via Propargyl Ketone
Derivatives
Scheme 2. Optimization of the One-Pot
Coupling-Addition-Cyclocondensation Synthesis of
4-Iodopyrrole 4a
Halopyrroles14,15 are valuable synthetic building blocks
for synthetic transformations, and therefore, a multicompo-
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Org. Lett., Vol. 11, No. 11, 2009

Table 1. Optimization of the Final Addition-Cyclocondensation
Step within the One-Pot Three-Component Synthesis of
4-Iodopyrrole 4a
Table 2. One-Pot Three-Component Synthesis of 4-Iodopyrroles
4
PTSA · H2O
added
reaction
4-iodopyrrole 4a
entry
(equiv)
cosolvent time (h) (isolated yield, %)
1
2
3
4
1.0
1.0
2.0
2.0
MeOH
22a
19a
19
1
60
65
70
69
t-BuOH
t-BuOH
t-BuOH
a After 1 h the reaction was not complete according to TLC monitoring.
(Table 1). The best conditions smoothly provided the desired
product 4a in 69% isolated yield within 1 h upon applying
2 equiv of PTSA·H2O and t-BuOH as the alcoholic additive
(entry 4). Interestingly, the yields of 4a were higher than
that of the isolated intermediate ynone 3a.16
With this mild, quick and practical protocol in hand we
set out to screen the scope of this reaction (Scheme 3, Table
Scheme 3
.
One-Pot Three-Component Synthesis of
4-Iodopyrroles 4
2). Upon upscaling to a 5 mmol level, an even higher yield
of the 4-iodopyrrole 4a can be obtained (Table 2, entry 1 vs
Table 1, entry 4). Further upscaling to 30 mmol furnished
compound 4d in 77% isolated yield (73% yield on the 5
mmol scale, Table 2, entry 4). The structures of the
4-iodopyrroles 4 were unambiguously assigned by spectro-
scopic characterization and combustion analysis and later
corroborated by an X-ray crystal structure analysis for
compound 4d (Figure 1).17
The sequence starts with easily accessible starting materials
and gives good yields of 4-iodopyrroles 4, and it is easy to
perform with a simple catalyst system and under mild
conditions.18 It was found to be quite general with respect
to the underlying acid chlorides 1. Aromatic substituents
bearing electroneutral (entry 5), electron-withdrawing (entries
6 and 7), and electron-donating (entries 1-4) substituents
even in the ortho-position (entry 3) are tolerated. Further-
more, heteroaryl (entry 8), alkenyl (entry 9), cyclopropyl
(entry 10), and sterically demanding adamantyl (entry 11)
substituents can be effectively carried through the sequence.
a All reactions were performed on 5 mmol scale. b The reaction time
for the coupling step was 21 h. c The reaction time for the coupling step
was 3 h.
However, for nonaromatic acid chlorides, the reaction times
of coupling were slightly longer than 1 h.
(9) (a) Willy, B.; Mu¨ller, T. J. J. ARKIVOC 2008, 1, 195. (b) Mu¨ller,
T. J. J. Chim. Oggi/Chem. Today 2007, 25, 70. (c) Mu¨ller, T. J. J. Targets
Heterocycl. Systems 2006, 10, 54.
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A. D.; Bonacorso, H. G.; Martins, M. A. P.; Wessjohann, L. A. J. Org.
Chem. 2006, 71, 6996. (c) Rosenmund, P.; Gru¨bel, K. Angew. Chem. 1968,
80, 702.
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D’Souza, D. M.; Mu¨ller, T. J. J. Nat. Protoc. 2008, 3, 1660.
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1502. (b) Karpov, A. S.; Mu¨ller, T. J. J. Synthesis 2003, 2815.
(8) D’Souza, D. M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095.
Org. Lett., Vol. 11, No. 11, 2009
2271

performed in the sense of a sequentially Pd/Cu-catalyzed
reaction20 since the catalyst system should be still operative
after the coupling-addition-cyclocondensation sequence.
Therefore, just upon addition of another terminal alkyne 5
to the reaction mixture, N-Boc-2-aryl-4-alkynylpyrroles 6
were obtained in good yields (Scheme 4). The conditions
Scheme 4
.
Coupling-Addition-Cyclocondensation-Coupling
Sequence to 4-Alkynyl-N-Boc-pyrroles 6
Figure 1. ORTEP plot of compound 4d.
The obtained 4-iodopyrroles 4 are highly useful synthetic
building blocks,19 and the first scouting experiments were
(12) (a) Karpov, A. S.; Merkul, E.; Oeser, T.; Mu¨ller, T. J. J. Eur. J.
Org. Chem. 2006, 2991. (b) Karpov, A. S.; Merkul, E.; Oeser, T.; Mu¨ller,
T. J. J. Chem. Commun. 2005, 2581.
are sufficiently mild to leave the Boc group uncleaved. In
comparison to the coupling-addition-cyclocondensation-
coupling one-pot synthesis (58% yield), the two-step syn-
thesis of the alkynyl pyrrole 6a furnishes a comparable
overall yield (61%).
In conclusion, we disclose an efficient one-pot three-
component synthesis of 2-substituted N-Boc-4-iodopyrroles
that can easily be upscaled to multigrams, and we also show
preliminary examples of a coupling-addition-cycloconden-
sation-coupling sequence to 4-alkynyl-N-Boc-pyrroles in
good yields. This latter principle appears to be quite general
and further terminating cross-coupling reactions can be easily
envisioned. Studies taking advantage of this versatile one-
pot multicomponent strategy to iodopyrroles as valuable
building blocks for the synthesis of 2,4-disubstituted pyrrole
derivatives are currently underway.
(13) (a) Merkul, E.; Grotkopp, O.; Mu¨ller, T. J. J. Synthesis 2009, 502.
(b) Merkul, E.; Mu¨ller, T. J. J. Chem. Commun. 2006, 4817.
(14) For noncatalytic accesses to halopyrroles from ynones, see: (a)
Ghosez, L.; Franc, C.; Denonne, F.; Cuisinier, C.; Touillaux, R. Can.
J. Chem. 2001, 79, 1827. (b) Franc, C.; Denonne, F.; Cuisinier, C.; Ghosez,
L. Tetrahedron Lett. 1999, 40, 4555. (c) Masquelin, T.; Obrecht, D. Synthesis
1995, 276.
(15) For coupling reactions with iodopyrroles, see: Liu, J.-H.; Chan,
H.-W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3274.
(16) The alkynone 3a can be isolated and was obtained in 59% yield.
(17) Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication nos. CCDC 723307
(4d). Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: + 44-1223/336-
033; E-mail: deposit@ccdc.cam.ac.uk).
(18) Typical procedure (4d). PdCl2(PPh3)2 (70 mg, 0.10 mmol) and
CuI (39 mg, 0.20 mmol) were placed under argon in a flame-dried screw-
cap vessel. Then 25 mL of dry THF was added, and the mixture was
degassed with argon. Dry triethylamine (0.69 mL, 5.00 mmol), 4-meth-
oxybenzoyl chloride (1d) (879 mg, 5.00 mmol), and tert-butyl prop-2-
ynylcarbamate (2) (776 mg, 5.00 mmol) were successively added to the
mixture which was then stirred at room temperature for 1 h. Then, sodium
iodide (3.79 g, 25.0 mmol), toluene-4-sulfonic acid monohydrate (1.94 g,
10.0 mmol), and 5 mL of tert-butyl alcohol were successively added to the
mixture, which was stirred at room temperature for 1 h. The reaction mixture
was diluted with 50 mL of brine, the phases were separated, and the aqueous
phase was extracted with dichloromethane (3 × 25 mL). The combined
organic layers were dried with anhydrous sodium sulfate. After removal of
the solvents in vacuo, the residue was absorbed onto Celite and chromato-
graphed on silica gel with petroleum ether (boiling range 40-60 °C)/ethyl
acetate (PE-EE ) 100:1) to give 1.46 g (73%) of analytically pure tert-
butyl 4-iodo-2-(4-methoxyphenyl)-1H-pyrrole-1-carboxylate (4d) as a color-
less solid: mp 71-72 °C; 1H NMR (CDCl3, 500 MHz) δ 1.39 (s, 9 H),
3.82 (s, 3 H), 6.20 (d, J ) 1.9 Hz, 1 H), 6.88 (d, J ) 8.8 Hz, 2 H), 7.24 (d,
J ) 8.8 Hz, 2 H), 7.39 (d, J ) 1.9 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 27.6 (CH3), 55.3 (CH3), 64.4 (Cquat), 84.2 (Cquat), 113.1 (CH), 120.3 (CH),
125.3 (Cquat), 126.7 (CH), 130.4 (CH), 136.5 (Cquat), 147.9 (Cquat), 159.3
(Cquat); EI + MS ( /z) 399 (M+, 3), 343 ((M - C4H8)+, 11), 299 ((M -
C5H8O2)+, 16), 298 ((M - C5H9O2)+, 13), 171 ((M - C5H9O2I)+, 6), 156
(12), 128 (11), 57 (C4H9+, 100), 41 (34); IR (KBr) ν˜ 1734 cm-1, 1511,
1370, 1337, 1293, 1251, 1180, 1151, 1032, 847, 808. Anal. Calcd for
C16H18INO3 (399.2): C, 48.14; H, 4.54; N, 3.51. Found: C, 48.36; H, 4.37;
N, 3.34.
Acknowledgment. The financial support of this work by
Merck Serono, Darmstadt, and the Fonds der Chemischen
Industrie is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 3a, 3b, 4, and
6. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL900581A
(19) Boc as an electron-withdrawing group allows the 4-iodopyrroles
4, which are notoriously unstable with electron-donating groups at the
pyrrole nitrogen, to be handled. They are storable for months in refrigerator
under argon without decomposition.
(20) (a) For a review, see e.g.: Mu¨ller, T. J. J. Top. Organomet. Chem.
2006, 19, 149. (b) For recent examples, see e.g.: Liao, W.-W.; Mu¨ller, T. J. J.
Synlett 2006, 3469. (c) See also ref 12b.
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Org. Lett., Vol. 11, No. 11, 2009