Co2(CO)8-catalyzed intramolecular hetero-Pauson-Khand reaction of alkynecarbodiimide: Synthesis of (±)-physostigmine

Article abstract of DOI:10.1021/ol052562z

(Chemical Equation Presented) Herein we describe a novel Co ₂(CO)₈-catalyzed intramolecular aza-Pauson-Khand-type reaction of alkynecarbodiimide derivatives affords pyrrolo-[2,3-b]indol-2-one ring systems in reasonable yields. This i

Full text of DOI:10.1021/ol052562z

ORGANIC
LETTERS
2006
Vol. 8, No. 1
83-86
Co2(CO)8-Catalyzed Intramolecular
Hetero-Pauson Khand Reaction of
Alkynecarbodiimide: Synthesis of
)-Physostigmine
−
(±
Chisato Mukai,*,† Tatsunori Yoshida,† Mao Sorimachi,† and Akira Odani‡
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan, and
Research Center for Materials Science, Graduate School of Sciences, Nagoya
UniVersity, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received October 21, 2005
ABSTRACT
Herein we describe a novel Co2(CO)8-catalyzed intramolecular aza-Pauson
[2,3-b]indol-2-one ring systems in reasonable yields. This is the first reported Co2(CO)8 successfully applied in the hetero-Pauson
reaction. Significantly, the transformation of one of our pyrrolo[2,3-b]indol-2-one derivatives into the indole alkaloid, (
completed in a highly stereoselective manner.
−
Khand-type reaction of alkynecarbodiimide derivatives affords pyrrolo-
Khand
)-physostigmine, was
−
±
The intramolecular Pauson-Khand reaction1 is well recog-
nized as one of the most straightforward and powerful
methodologies for the construction of bicyclic carbon
frameworks. This intriguing reaction is a formal metal-
mediated (or catalyzed) [2 + 2 + 1]-cycloaddition reaction
of the alkyne π-bond, the alkene π-bond, and carbon
monoxide. The reaction would generally be referred to as
the “hetero-Pauson-Khand reaction” if more than one carbon
atom of the newly generated cyclopentenone framework was
replaced by an oxygen atom and/or nitrogen functionalities.
Thus, the hetero-Pauson-Khand reaction would be realized
for the oxa(aza)alkyne and/or an oxa(aza)alkene counterpart
that could take part in the [2 + 2 + 1]-cycloaddition reaction.
The first hetero-Pauson-Khand-type reactions were inde-
pendently achieved by Buchwald’s2 and Crowe’s groups3 in
1996, via the intramolecular titanium-mediated [2 + 2 +
1]-cycloaddition of δ-unsaturated ketones and aldehydes
(between the alkene π-bond and the oxa-alkene π-bond) with
carbon monoxide, which resulted in the formation of bicyclic
† Kanazawa University.
‡ Nagoya University.
(1) For leading reviews, see: (a) Pauson, P. L. In Organometallics in
Organic Synthesis. Aspects of a Modern Interdisciplinary Field; de Meijere,
A., tom Dieck, H., Eds.; Springer: Berlin, 1988; pp 233-246. (b) Schore,
N. E. Chem. ReV. 1988, 88, 1081-1119. (c) Schore, N. E. Org. React.
1991, 40, 1-90. (d) Schore, N. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5, pp 1037-1064. (e)
Schore, N. E. In ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol.
12, pp 703-739. (f) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523-596. (g)
Jeong, N. In Transition Metals in Organic Synthesis; Beller, H., Bolm, C.,
Eds; Wiley-VCH: Weinheim, 1998; Vol. 1, pp 560-577. (h) Geis, O.;
Schmalz, H.-G. Angew. Chem., Int. Ed. 1998, 37, 911-914. (i) Chung, Y.
K. Coord. Chem. ReV. 1999, 188, 297-341. (j) Brummond, K. M.; Kent,
J. L. Tetrahedron 2000, 56, 3263-3283. (k) Bon˜aga, L. V. R.; Krafft, M.
E. Tetrahedron 2004, 60, 9795-9833.
(2) (a) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 5818-5819. (b) Kablaoui, N. M.; Hicks, F. A.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 4424-4431.
(3) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557-1558.
10.1021/ol052562z CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/08/2005

γ-lactone species (oxa-Pauson-Khand-type reaction). Sev-
eral years later, Chatani and Murai4 discovered that Ru3-
(CO)12 could efficiently catalyze not only the intramolecular
oxa-Pauson-Khand reaction but also the aza-Pauson-Khand
reaction to provide R,â-unsaturated γ-butenolides4a from the
ynealdehydes (between alkyne π-bond and oxa-alkene
π-bond), and the R,â-unsaturated lactams4b from the yne-
imines (between alkyne π-bond and aza-alkene π-bond),
respectively. To the best of our knowledge, this Ru3(CO)12-
catalyzed reaction is the first example of the metal-catalyzed
hetero-Pauson-Khand reaction. Ru3(CO)12 was also found
by Kang5 to be effective for the intramolecular oxa-Pauson-
Khand-type reaction of the δ-allenyl carbonyl congeners
(instead of the ynealdehydes) to afford the corresponding
R-methylene-γ-butyrolactones. Kang’s group5 also reported
that the δ-allenyl moiety participated in the intramolecular
aza-Pauson-Khand-type reaction with N-benzoylhydrazones
(between allene π-bond and aza-alkene π-bond). A similar
transformation of the δ-allenylcarbonyl compounds into the
R-methylene-γ-butyrolactones under the Mo(CO)6-mediated
conditions was developed by Yu’s group.6 In addition, Saito7
recently reported a new type of aza-Pauson-Khand reaction,
involving the cyclocarbonylation of the alkyne carbodiimide
substrates 1 (between alkyne π-bond and carbodiimide
π-bond) to provide the diazabicyclic compounds 2 under the
Mo(CO)6-mediated conditions (stoichiometric version)
(Scheme 1).
an isoelectronic alternative to the allenyl moiety in the
Pauson-Khand-type reaction (aza-Pauson-Khand-type re-
action), although Saito7 already developed the stoichiometric
procedure using Mo(CO)6. Thus, we focused our efforts on
the development of a new metal-catalyzed intramolecular
aza-Pauson-Khand-type reaction of the N-[2-(1-alkynyl)-
phenyl]-N′-phenylcarbodiimide derivatives.9 This letter de-
scribes the preliminary results of (i) the novel Co2(CO)8-
catalyzed intramolecular aza-Pauson-Khand-type reaction
of N-[2-(1-alkynyl)phenyl]-N′-phenylcarbodiimide deriva-
tives to obtain the pyrrolo[2,3-b]indol-2-one framework in
onestep and (ii) a short and reasonably rapid synthesis of
(()-physostigmine10 based on the thus-developed catalytic
aza-Pauson-Khand-type product. We note, in advance, that
this is the first example of the Co2(CO)8-catalyzed aza-[2 +
2 + 1] cycloaddition process ever reported.
The required alkynecarbodiimide substrates 5 for the
cyclocarbonylation were prepared in a straightforward man-
ner from the known 2-alkynylaniline derivatives 3. Treatment
of 3 with triphosgene and Et3N was followed by exposure
to primary amines11 afforded the urea derivatives 4 in high
yield. Exposure of 4 to carbon tetrabromide and triph-
enylphosphine12 effected dehydration to provide the carbo-
diimides 5 as shown in Scheme 2.
Scheme 2
Scheme 1
Our recent interest8 in the development of rhodium-
catalyzed intramolecular Pauson-Khand-type reactions be-
tween the alkyne π-bond and the allene π-bond (instead of
the olefin π-bond) led to an easy preparation of the bicyclo-
[4.3.0]nonadienone as well as bicyclo[5.3.0]decadienone
frameworks. We have now become very interested in the
metal-catalyzed cyclocarbonylation between the alkyne
π-bond and the diaza-allene π-bond (carbodiimide function-
ality) because the carbodiimide group might be regarded as
Our initial evaluation of the metal-catalyzed cyclocarbo-
nylation of an alkynecarbodiimide was carried out using
compound 5a (Table 1). Chatani and Murai’s conditions
(catalytic amounts of Ru3(CO)12 in toluene at 120 °C under
10 atm of CO)4 were first applied to compound 5a to afford
the desired pyrrolo[2,3-b]indol-2-one 6a in 35% yield along
with the urea 4a in 27% yield13 (entry 1).
[RhCl(CO)2]2,8 a suitable catalyst for the ring-closing
reaction between the alkyne and allene groups, gave 6a in a
(4) (a) Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 1998, 120, 5335-5336. (b) Chatani, N.; Motimoto, T.; Kamitani, A.;
Fukumoto, Y.; Mutai, S. J. Organomet. Chem. 1999, 579, 177-181.
(5) Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Angew. Chem., Int. Ed. 2002,
41, 1584-1586.
(6) Yu, C.-M.; Hong, Y.-T.; Lee, J.-H. J. Org. Chem. 2004, 69, 8506-
8509.
(7) Saito, T.; Shiotani, M.; Otani, T.; Hasaba, S. Heterocycles 2003, 60,
1045-1048.
(8) (a) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett.
2002, 4, 1755-1758. (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem.
2003, 68, 1376-1385. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S.
Tetrahedron Lett. 2004, 45, 4117-4121. (d) Mukai, C.; Inagaki, F.; Yoshida,
T.; Yoshitani, K.; Hara, Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159-
7171.
(9) The thermal transformation of the N-[2-(1-alkynyl)phenyl]-N′-phe-
nylcarbodiimides into the 6H-indolo[2,3-b]qinolines via the biradical
intermediates and its related reactions were reported; see: (a) Schmittel,
M.; Steffen, J.-P.; Engels, B.; Lennartz, C.; Hanrath, M. Angew. Chem.,
Int. Ed. 1998, 37, 2371-2373. (b) Shi, C.; Zhang, Q.; Wang, K. K. J. Org.
Chem. 1999, 64, 925-932. (c) Zhang, Q.; Shi, C.; Zhang, H.-R.; Wang, K.
K. J. Org. Chem. 2000, 65, 7977-7983. (d) Schmittel, M.; Rodr´ıguez, D.;
Steffen, J.-P. Angew. Chem., Int. Ed. 2000, 39, 2152-2155. (e) Lu, X.;
Petersen, J. L.; Wang, K. K. J. Org. Chem. 2002, 67, 5412-5415. (f) Lu,
X.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2002, 67, 7797-7801. (g)
Li, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2003, 68, 5512-5518.
(h) Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2004, 69,
4500-4508.,
84
Org. Lett., Vol. 8, No. 1, 2006

Table 1. Aza-Pauson-Khand Reaction of Carbodiimide 5a
Table 2. Aza-Pauson-Khand Reaction of Carbodiimide 5b-k
with Co2(CO)8
a
a A mixture of carbodiimide 5, Co2(CO)8 (10 mol %), and TMTU (60
mol %) in benzene (0.1 M) was heated at 70 °C under an atmosphere of
CO. b Co2(CO)8 (20 mol %) and TMTU (120 mol %) were used.
a DMSO (6.0 equiv) was used. b TMANO (4.0 equiv) was used.
c Reaction temperature was warmed to rt. d TMTU (60 mol %) was used.
e DMSO (10 equiv) was used.
lecular ring-closing step of 5a to furnish the pyrrolo[2,3-b]-
indol-2-one framework 6a.
low yield (entry 2). Co2(CO)814 consistently provided 6a as
the major product (entries 3-6). In particular, 6a was
obtained in 69% yield when 5a was exposed to 10 mol %
Co2(CO)8 and tetramethylthiourea (TMTU)14e in benzene at
70 °C under an atmosphere of CO (entry 6). A control
experiment using a combination of Mo(CO)6 and DMSO at
80 °C in toluene7,15 produced 6a in 76% yield together with
a small amount of 4a13 (entry 7). Thus, a catalytic amount
of Co2(CO)8 was found to efficiently accelerate the intramo-
Scheme 3
(10) For recent total synthesis of physostigmine, see: (a) Node, M.; Hao,
X.; Nishide, K.; Fuji, K. Chem. Pharm. Bull. 1996, 44, 715-719. (b)
Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6500-6503. (c) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000,
2, 675-678. (d) ElAzab, A, S.; Taniguchi, T.; Ogasawara, K. Org. Lett.
2000, 2, 2757-2759. (e) Tanaka, K.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2001, 42, 1049-1052. (f) M.-Rios, M. S.; S.-Sanchez,
N. F.; J.-Nathan, P. J. Nat. Prod. 2002, 65, 136-141. (g) Mekhael, M. K.
G.; Heimgartner, H. HelV. Chim. Acta 2003, 86, 2805-2813. (h) Rage, P.
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(12) Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron
1999, 55, 4325-4340.
(13) The formation of the urea derivative 4 as a byproduct could
tentatively be interpreted by hydrolysis with a small amount of water
inevitably present in the reaction medium.
(14) (a) Hoye, T. R.; Suriano, J. A. J. Org. Chem. 1993, 58, 1659-
1660. (b) Jiang, B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43, 2543-2546.
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Org. Lett., Vol. 8, No. 1, 2006
85

We next investigated the scope of this ring-closing reaction
using various substrates 5b-k under the Co2(CO)8-catalyzed
conditions (Table 2). The carbodiimides 5b,i-k, having the
phenyl substitutent on the nitrogen atom (R3) as well as the
TMS group at the alkyne terminus (R2), consistently pro-
duced the corresponding pyrrolo[2,3-b]indol-2-one skeleta
6b,i-k in reasonable yield (more than 50%) irrespective of
the substituent (R1) on the benzene ring (entries 1,8-10).The
carbon appendages at the triple bond terminus, such as a
propyl (entry 4), aklenyl (entry 5), and siloxyethyl (entry 6)
were stable under the CO2(CO)8-catalyzed conditions and
the corresponding cyclocarbonylated products 5e-g were
obtained in good yields. However, the benzyl and alkyl
substituents on the nitrogen atom (R3) 5c,d provided the
cyclized products 6c,d in slightly lower yields (entries 2,3).
The propargyl alcohol derivative 5h was shown to be a poor
substrate for this catalytic ring-closing reaction (entry 7).
was achieved by the conventional procedures via the iodo
derivative 12 in high yields. The present synthesis of 13
amounts to the synthesis of (()-physostigmine (14),10,21
since the former has already been converted into the latter
(Scheme 3).
In summary, we have developed the novel Co2(CO)8-
catalyzed aza-Pauson-Khand-type reaction of alkynecarbo-
diimide derivatives to give a range of pyrrolo[2,3-b]indol-
2-one skeleta. This is the first demonstration of the use of
Co2(CO)8 in the hetero-Pauson-Khand reaction. In addition,
a new synthesis of (()-physostigmine, involving a one-step
construction of the core framework, followed by a small
number of chemical modifications, has been achieved.
Acknowledgment. This work was supported in part by
a Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
for which we are thankful.
Our application of the newly developed catalytic aza-
Pauson-Khand-type reaction for the synthesis of natural
products is the next subject. According to the Co2(CO)8-
catalyzed cyclocarbonylation conditions, the pyrrolo[2,3-b]-
indol-2-one 9 was prepared in 55% yield16,17 yield from the
carbodiimide 8.18 Reductive methylation of 9 with NaCNBH3
in the presence of aq HCHO and AcOH effected the con-
secutive reduction, hydroxymethylation, and N-methylation
to produce 1019 in 79% yield as a single stereoisomer.20
Removal of a TMS group from 10 with TBAF gave 11 in
96% yield, conversion of which into (()-esermethole (13)10,21
Supporting Information Available: General procedures
for ring-closing reaction and preparation of ureas and
carbodiimides, and characterization data for compounds 4a-
1
k, 5a-k, 6a-k, and 7-13. H and 13C spectra for com-
pounds 4b,d, 5a-k, 8, 12, and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052562Z
(19) A full mechanistic discussion is premature at this point, but the
one-step transformation of 9 into 10 might be rationalized in terms of the
initial attack of the hydride species at the C3-position (1,4-reduction) of 9
resulting in the formation of the indole intermediate, which subsequently
reacted with HCHO at the C3a-position to give the corresponding indolenine
derivative. The formed imine moiety (N8-C8a) would be susceptible to the
hydride reduction, followed by N-methylation to produce 10.
(20) The relative stereochemistry of 10 was determined by an NOE
experiment.
(16) Co2(CO)8 (20 mol %) was used.
(17) A stoichiomeric amount of Mo(CO)6 (1.2 equiv) and DMSO (10
equiv) afforded the desired 9 in 78% yield along with the urea 7 in 8%
yield.
(18) Coumpound 8 was prepared from 3j via 7.
(21) Yu, Q.-S.; Brossi, A. Heterocycles 1988, 27, 745-750.
86
Org. Lett., Vol. 8, No. 1, 2006