Rhodium(I)-catalyzed [2+2+2] cycloadditions with N-functionalized 1- alkynylamides: A conceptually new strategy for the regiospecific synthesis of substituted indolines

Article abstract of DOI:10.1002/(SICI)1521-3773(19990816)38:16<2426::AID-ANIE2426>3.0.CO;2-Y

The regiospecific introduction of substituents into the 4-position of 2,3-dihydroindoles (indolines), which is significant for the synthesis of various natural products and pharmaceuticals, was achieved by rhodium(I)- catalyzed cyclotrimerizations of 1 wi

Full text of DOI:10.1002/(SICI)1521-3773(19990816)38:16<2426::AID-ANIE2426>3.0.CO;2-Y

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Table 2. Biological activity (IC50) for HIV-1 RT inhibition, L1210 and
HCT116 cytotoxic activity.
1980, 33, 1098; Sandramycin: J. A. Matson, J. A. Bush, J. Antibiot.
1989, 42, 1763; J. A. Matson, K. L. Colson, G. N. Belofsky, B. B.
Bleiberg, J. Antibiot. 1993, 46, 162.
Compound
HIV-1 RT[a]
L1210[b]
HCT116[c]
[4] E. Arnold, J. Clardy, J. Am. Chem. Soc. 1981, 103, 1243; M. Konishi, H.
Ohkuma, F. Sakai, T. Tsuno, H. Koshiyama, T. Naito, H. Kawaguchi, J.
Am. Chem. Soc. 1981, 103, 1241.
[5] Luzopeptins A ± C: D. L. Boger, M. W. Ledeboer, M. Kume, J. Am.
Chem. Soc. 1999, 121, 1098; Sandramycin: D. L. Boger, J.-H. Chen, J.
Am. Chem. Soc. 1993, 115, 11624; D. L. Boger, J.-H. Chen, K. W.
Saionz, J. Am. Chem. Soc. 1996, 118, 1629.
[mm]
[nm]
[nm]
1
2
3
4
0.6
0.9
0.3
6
0.3
2
> 100
0.008
30
1
7
> 100
0.3
30
5
3
[6] D. L. Boger, G. Schüle, J. Org. Chem. 1998, 63, 6421.
6
11
13
14
0.4
0.7
0.9
0.8
2
> 100
> 100
6
> 100
n.d.[d]
[7] EDCI ˆ 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlor-
ide, HOBt ˆ 1-hydroxybenzotriazole, SES ˆ 2-(trimethylsilyl)ethyl-
sulfonyl, TBS ˆ tert-butyldimethylsilyl.
2
> 100
7
[8] B. A. Dumaitre, N. Dodic, A. C. M. Daugan, P. M. C. Pianetti (Glaxo
S.A.), WO-A 9401408, 1994 [Chem. Abstr. 1995, 122, 31342e].
[9] I. Arai, A. Mori, H. Yamamoto, J. Am. Chem. Soc. 1985, 107, 8254; A.
Mori, I. Arai, H. Yamamoto, Tetrahedron 1986, 42, 6447. The acid
chlorides were prepared from the corresponding carboxylic acids
(0.9 equiv (COCl)2, cat. DMF, CH2Cl2, 08C for 10 ± 15 min, 258C for
1 ± 2 h) and used directly. For the carboxylic acid precursor to (1R,2R)-
Sandramycin
0.001
0.007
[a] HIV-1 reverse transcriptase inhibition. [b] L1210 mouse leukemia cyto-
toxic assay. [c] Human colon carcinoma assay. [d] n.d. ˆ not determined.
10: [a]2D3
ˆ
74.4 (c ˆ 0.29, EtOH), literature value [a]D24
ˆ
71.9 (c ˆ
possessing the unnatural (R,R)-2-methylcyclopropane car-
boxylic acid substituent proved to be only slightly less potent
than natural quinoxapeptin A (1) in both the HIV-1 RT and
cytotoxic assays. In addition, the quinoxapeptins displayed
activity trends analogous to those observed with the luzo-
peptins with the important exception that the RT inhibition
was more potent and the cytotoxic activity less potent
enhancing the selective RT inhibition observed with the
quinoxapeptins. The comparison of the quinoxapeptin deriv-
ative 14 with luzopeptin A (4) is instructive in this regard,
where 14 was nearly 10-fold more potent against HIV-1 RT
and 1000 times less potent in the L1210 cytotoxic assay. The
HIV-1 RT inhibition follows the trend of quinoxapeptin C >
A analogous to the luzopeptin C > B > A potency with the l-
Htp free alcohols being the most active agents in each series.
A reverse potency order was observed in the cycotoxic assays
with quinoxapeptin A ꢀ C and luzopeptin A > B ꢀ C with
the l-Htp free alcohols being inactive. Thus, the synthetic
precursor 3 (quinoxapeptin C), which has not yet been
disclosed as a natural product, exhibits the most potent
HIV-1 RT inhibition in the series and lacks a dose-limiting in
vitro cytotoxic activity making it the most attractive member
of the series examined to date.
1.00, EtOH). For the carboxylic acid precursor to (1S,2S)-10: [a]D23
ˆ
‡75.6 (c ˆ 0.25, EtOH). The 13C NMR of 1 and 2 proved diagnostic of
a trans versus cis 2-methylcyclopropane carboxylic acid ester (d ˆ 18
versus d ˆ 12 for CH3) limiting the possibilities to (1R,2R)-10 or
(1S,2S)-10.
[10] D. L. Boger, J.-H. Chen, K. W. Saionz, Q. Jin, Bioorg. Med. Chem.
1998, 6, 85; D. L. Boger, K. W. Saionz, Bioorg. Med. Chem. 1999, 7,
315.
[11] D. L. Boger, J.-H. Chen, Bioorg. Med. Chem. Lett. 1997, 7, 919.
Rhodium(I)-Catalyzed [2‡2‡2]
Cycloadditions with N-Functionalized
1-Alkynylamides: A Conceptually New
Strategy for the Regiospecific Synthesis of
Substituted Indolines**
Bernhard Witulski* and Thomas Stengel
Received: March 12, 1999 [Z13157IE]
German version: Angew. Chem. 1999, 111, 2533 ± 2536
Stereoselective syntheses of multifunctionalized indoles
and indolines (2,3-dihydroindoles) are a continuous challenge
because of the enormous relevance of this class of compounds
in the fields of natural products, pharmaceuticals, and drug-
related targets.[1] Substructures of highly functionalized in-
doles are found in numerous natural products and pharma-
ceutically active compounds, for instance in the ergot
alkaloids,[2] the telocidines,[3] the diazonamides[4] as well as
in N-methylwelwitindolinone C,[5] an indolinone alkaloid that
Keywords: antitumor agents ´ natural products ´ peptides ´
structure-activity relationships ´ total synthesis
[1] R. B. Lingham, A. H. M. Hsu, J. A. OꢁBrien, J. M. Sigmund, M.
Sanchez, M. M. Gagliardi, B. K. Heimbuch, O. Genilloud, I. Martin,
M. T. Diez, C. F. Hirsch, D. L. Zink, J. M. Liesch, G. E. Koch, S. E.
Gartner, G. M. Garrity, N. N. Tsou, G. M. Salituro, J. Antibiot. 1996,
49, 253.
[2] G. M. Garrity, O. Genilloud, A. H. M. Hsu, R. B. Lingham, B. Russell,
I. Martin, G. M. Salituro, M. Sanchez, J. M. Sigmund, N. N. Tsou
(Merck), GB-B 2294265, 1996 [Chem. Abstr. 1996, 125, 112914g].
[3] Luzopeptins A ± C: M. Konishi, H. Ohkuma, F. Sakai, T. Tsuno, H.
Koshiyama, T. Naito, H. Kawaguchi, J. Antibiot. 1981, 34, 148; H.
Ohkuma, F. Sakai, Y. Nishiyama, M. Ohbayashi, H. Imanishi, M.
Konishi, T. Miyaki, H. Koshiyama, H. Kawaguchi, J. Antibiot. 1980, 33,
1087; K. Tomita, Y. Hoshino, T. Sasahira, H. Kawaguchi, J. Antibiot.
[*] Dr. B. Witulski, Dipl.-Chem. T. Stengel
Fachbereich Chemie der Universität
Erwin-Schrödinger-Straûe, D-67663 Kaiserslautern (Germany)
Fax : (‡ 49)631-205-3921
E-mail: bernhard@chemie.uni-kl.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Wi 1696/1 ± 1 und 1 ± 2). We thank Prof. Dr. M. Regitz for his
generous support.
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reverses the multiple-drug-resistance of vinblastine-resistant
adenocarcinoma cells.
after deprotonation of the amides 1[11] with n-butyllithium or
potassium hexamethyldisilazide (KHMDS), followed by the
addition of the alkynyliodonium salts[12] 2a ± c in toluene. In
addition to the previously utilized 2a (R2 ˆ SiMe3), the
alkynyliodonium salt 2b (R ˆ Ph), and the parent compound
2c (R ˆ H) could be applied as reagents for an efficient
ethynylation process (entries 7 ± 9, and 11 in Table 1).[13]
Desilylation of 3 with tetrabutylammonium fluoride (TBAF)
in wet THF gave the terminal diynes 4 in yields of between 65
and 90%.
While the functionalization of the indole or indoline ring
system through reactions with electrophiles is often limited to
the electronically activated (3-), 5-, and 7-positions, the
regioselective functionalization of the 4-positionÐmost sig-
nificant for the synthesis of various natural products and
pharmaceuticalsÐis in many cases difficult.[1, 6] Syntheses of
multifunctionalized indoles and indolines based on annulation
strategies[1, 7] are equally laborious since they may be encum-
bered with the disadvantages of moderately pronounced
regioselectivities and multistep syntheses of the correspond-
ing highly functionalized benzene precursors.
Table 1. Products of the ethynylation of 1 with the alkynyliodonium salts
2a ± c.
Here we report a conceptually new strategy for the
synthesis of multifunctionalized indolines that is based on
transition metal catalyzed [2 ‡ 2 ‡ 2] cycloadditions[8] which
utilize our recently reported N-functionalized and electroni-
cally tunable 1-alkynylamides as key building blocks.[9]
The design of this new indoline synthesis is based on the use
of N-(3-butynyl)-1-alkynylamides of type I in rhodium(I)-
catalyzed cyclotrimerizations[10] with differently substituted
monoalkynes; hence it should allow the regiospecific intro-
duction of functional groups into the 4- or 7-position as well as
into the 4- and 7-position of the indoline moiety. However, if
asymmetrically substituted monoalkynes are used as cyclo-
addition partners, two regioisomeric products should be
expected (Scheme 1).
Entry 1
R1[a]
2
R2
3
Yield [%][b]
1
2
1a
SiMe3
2a
2a
2a
2a
2a
2a
2c
2c
2b
2a
2b
2a
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
H
H
Ph
SiMe3
Ph
SiMe3
3a
3b
3c
3d
3e
3 f
3g
3h
3i
69
80
66
43
28
72
85
35
50
64
55
60
1b (CH2)2OTBDMS
3
1c
(CH2)2OBzl
4
1d (CH2)2OTHP
5
6
7
1e
1 f
1g
(CH2)2NHTs
Ph
Ph
8
1h CO2Me
9
1i
1j
H
H
10
11
12
3j
3k
3l
1k (CH2)2OBzl
1l CH2OTHP
[a] TBDMS ˆ tert-butyldimethylsilyl; THP ˆ tetrahydropyranyl. [b] Yields
obtained after column chromatography.
A
B
A
Significantly, the unsubstituted diyne 4a and its monosub-
stituted derivatives 4b ± e as well as 3g and 3h were
particularly suitable substrates for rhodium(I)-catalyzed
[2 ‡ 2 ‡ 2] cycloadditions with monoalkynes. Crossed cyclo-
trimerizations of 4a ± e and 3g (0.01 ± 0.03m) with acetylene
(1 atm) already occur at temperatures between 0 and 20oC in
toluene with 3 ± 5 mol% of [RhCl(PPh3)3] as catalyst. On the
contrary, the cyclotrimerization of acetylene with the diyne
3h, which bears an electron-withdrawing alkyne substituent,
required a temperature of 1108C to complete the reaction.
The resulting indolines 5a ± h were obtained in yields of 43 ±
91% after isolation by column chromatography on silica gel
(Table 2).[14] Apart from toluene, dichloromethane, ethanol,
and trifluoroethanol could be used as solvents.[15]
In addition to the regiospecific introduction of substituents
into the 4-position of the indoline core by rhodium(I)
catalysis, those of both the 7-position and the 4- and 7-position
succeeded in yields of 68 ± 95% (Table 3).[14] However, in
these cases cyclotrimerizations with acetylene go to comple-
tion only when carried out at 100oC in a sealed Schlenk tube
and with catalyst loadings of 5 ± 10 mol% [RhCl(PPh3)3].
Evidently a substituent at the N-1-alkynylamide moiety
causes a decrease in effectiveness of the cycloadditions with
acetylene.
4
D
C
C
D
C
D
A
B
2
+
catalyst
N
N
N
6
Ts
Ts
Ts
B
I
III
II
Scheme 1. Strategy for the synthesis of multifunctionalized indolines by
[2 ‡ 2 ‡ 2] cycloadditions. Ts ˆ p-toluenesulfonyl.
The synthesis of the diynes 3 and 4 needed for the alkyne
cyclotrimerization studies relied on our recently developed
approach to N-functionalized 1-alkynylamides (Scheme 2 and
Table 1).[9] The diynes 3 are available in yields of 45 ± 80%
1) nBuLi or KHMDS
R1
R2
R1
2) toluene, 20 oC
N
NH
Ph
Ts
+
Ts
R2
I
-
OTf
3
1
desilylation
2a: R2 = SiMe3
2b: R2 = Ph
2c: R2 = H
TBAF, THF/H2O,
oC, (65-90%)
0
4
R1
H
H (1 atm)
4
3-10 mol% [RhCl(PPh3)3]
toluene
Initial results regarding the quest for a regioselective
functionalization of the 5- and 6-position of the indoline core
were obtained by cyclotrimerization studies with monosub-
stituted alkynes. Rhodium(I)-catalyzed [2 ‡ 2 ‡ 2] cycloaddi-
tions in toluene with 4a and the alkynols 6a ± c (5 equivalents)
yielded the indolines 7a,b, 8a,b, and 9a,b, respectively,
N
Ts
R2
5
Scheme 2. Synthesis of the N-(3-butynyl)-1-alkynylamides 3 and 4 and
their rhodium(I)-catalyzed cyclotrimerizations with acetylene. Tf ˆ tri-
fluoromethanesulfonyl.
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Table 2. Rhodium(I)-catalyzed [2 ‡ 2 ‡ 2] cycloadditions with acetylene
for the regiospecific synthesis of indolines with functional groups in the
4-position.
Table 3. Rhodium(I)-catalyzed [2 ‡ 2 ‡ 2] cycloadditions with acetylene
for the regiospecific synthesis of indolines with functional groups in the 7-,
as well as in the 4- and 7-position.
Entry Diyne
T [8C]
t [h]
Product (yield [%])[a]
Entry Diyne
T [8C]
t [h]
Product (yield [%])[a]
H
H
H
R
N
N
N
N
Ts
Ts
Ts
Ts
R
1
4a
20
0.5
5a (91)
1
2
3i: R ˆ Ph
110
110
24
18
5i: R ˆ Ph (85)
R
3j: R ˆ SiMe3
5j: R ˆ SiMe3 (68)
R
Ph
Ph
N
H
N
SiMe3
Ts
N
N
Ts
Ts
Ts
SiMe3
2
3
4
5
4b: R ˆ OH
4c: R ˆ OBzl
0
20
20
20
5
2
2
2
5b: R ˆ OH (70)
5c: R ˆ OBzl (55)
5d: R ˆ OTHP (57)
5e: R ˆ NHTs (65)
3
3f
110
18
5k (93)
OTHP
4d: R ˆ OTHP
4e: R ˆ NHTs
OTHP
SiMe3
N
N
Ts
Ts
SiMe3
4
3d
110
110
18
18
5l (95)
N
H
Ts
CO2Me
N
Ts
CO2Me
SiMe3
N
6
3g
20
3
2
5g (65)
N
Ts
Ts
CO2Me
SiMe3
CO2Me
H
5[b]
3m
5m (92)
N
N
Ts
[a] All reactions were carried out in acetylene-saturated toluene. Yields
refer to products obtained after column chromatography. [b] Compound
3m was obtained by carboxymethylation of 3j with cyanoformic acid
methyl ester.
Ts
7[b]
3h
110
5h (43)
[a] All reactions were carried out in acetylene-saturated toluene. Yields
refer to products obtained after column chromatography. [b] The reaction
was carried out in a sealed Schlenk flask.
hindrance (acceptance of hydrogen to trimethylsilyl groups),
electronic effects (compatibility of electron-withdrawing,
electron-donating, and conjugating substituents in the acety-
lene components), and functional group diversity (acceptance
of alcohol, ether, amide, and ester groups). The application of
terminal rather than non-terminal alkynes has only minor
effects with respect to reactivity and overall efficiency,
although the utilization of non-terminal diynes is sometimes
accompanied by higher yields (entries 6 and 7 in Table 2 and
entries 3 and 5 in Table 3, respectively). In addition to the
regiospecific functionalization of the 4- or the 7-position as
well as the 4- and 7-positions, the simultaneous introduction of
one to four substituents into the indoline core is possible with
one strategy.
without any preference for a particular regioisomer (entries
1 ± 3 in Table 4). On the contrary, cyclotrimerizations of the
alkynol 6b with the differently substituted diynes 3i and 3j
were accompanied by a substantial meta-selectivity, presum-
ably caused by steric interactions of the diyne and monoyne
substituents (entry 4 and 5 in Table 4).[16]
Furthermore, the simultaneous introduction of three or
four different substituents into the indoline ring system could
be achieved with this novel strategy as demonstrated by the
cyclotrimerization of diyne 3k with the monoalkynes 6b and
13. Surprisingly a pronounced selectivity (12a:12b ˆ 20:1)
was accomplished in the case of the cycloaddition of the diyne
3k with 6b.[17]
Even though the observed regioselectivities with respect to
the functionalization of the 5- and the 6-positions need further
investigations regarding the influence of the substitution
pattern and the catalyst, the following can be summarized: the
strategy outlined herein for the synthesis of multifunctional-
ized indolines by rhodium(I)-catalyzed [2 ‡ 2 ‡ 2] cycloaddi-
tions is compatible with a rich variety of substituents and a
pronounced structural diversity with regard to the obtainable
substitution pattern. The flexibility and efficiency of this
conceptually novel indoline synthesis, which is also based on
the efficient access to the diynes 3 and 4 through a direct
ethynylation process with the alkynyliodonium salts 2a ± c,
are illustrated by the examples in the Tables 2 ± 4. The
cyclotrimerizations are relatively insensitive towards steric
Experimental Section
5b: [RhCl(PPh3)3] (9 mg, 0.0097 mmol) was added to a solution of 4b
(64 mg, 0.22 mmol) in dry toluene (15 mL) saturated with acetylene (1 atm)
at 0 oC. The reaction mixture was stirred for 5 h at 0oC in an atmosphere of
acetylene (1 atm). The solvent was evaporated and the resulting crude
product purified by column chromatography (silica gel, hexanes:diethyl
etherˆ 1:1 (v/v)) to afford indoline 5b (49 mg, 0.15 mmol; 70%) as
colorless plates. M.p. 101 ± 102 oC (hexanes/diethyl ether); 1H NMR
(400 MHz, CDCl3/TMS): d ˆ 7.67 (d, J ˆ 8.2 Hz, 2H), 7.52 (d, J ˆ 8.2 Hz,
1H), 7.22 (d, J ˆ 7.9 Hz, 2H), 7.15 (t, J ˆ 7.9 Hz, 1H), 6.84 (d, J ˆ 7.4 Hz,
1H), 3.91 (t, J ˆ 8.4 Hz, 2H), 3.75 (ªdº, J ꢁ 4.6 Hz, 2H), 2.87 (t, J ˆ 8.4 Hz,
2H), 2.71 (t, J ˆ 6.7 Hz, 2H), 2.37 (s, 3H); 13C NMR (100.6 MHz, CDCl3):
d ˆ 144.04 (s), 142.04 (s), 135.16 (s), 133.93 (s), 130.86 (s), 129.61 (d), 128.06
(d), 127.30 (d), 124.23 (d), 113.03 (d), 62.28 (t), 49.73 (t), 36.08 (t), 26.57 (t),
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Table 4. Regioselectivity of rhodium(I)-catalyzed cyclotrimerizations.
Entry
Diyne
Monoalkyne[a]
T [8C]
Products (isomer ratio[b]
)
Yield [%][c]
OH
OH
(CH2)n
(CH2)n
+
N
N
(CH2)n
OH
Ts
Ts
H
1
2
3
4a
4a
4a
6a: n ˆ 1
6b: n ˆ 2
6c: n ˆ 3
20
20
20
7a ‡ 7b (1.3:1)
8a ‡ 8b (1.0:1)
9a ‡ 9b (1.0:1)
OH
60
85
63
+
N
N
Ts
Ts
R
R
OH
4
5
3i
3j
6b
6b
110
110
R ˆ Ph: 10a ‡ 10b (10:1)
68
60
R ˆ SiMe3: 11a ‡ 11b (2.7:1)
OBzl
OBzl
OH
+
N
N
H
Ts
Ts
Ph
Ph
OH
NOE
6
3k
3k
6b
110
40
12a ‡ 12b (20:1)
88
62
OH
BzlO
OH
N
Ts
OH
Ph OH
7[d]
13
15
[a] Cyclotrimerizations were run with 5 ± 6 equivalents of monoalkyne. [b] The isomer ratio was determined by NMR spectroscopy. [c] All reactions were
carried out in toluene. Yields refer to products obtained after column chromatography. In general the respective isomers, in the case of 10 ± 12 the main
product, can be obtained in an isomerically pure form by repeated chromatography. [d] The reaction was carried out in CH2Cl2.
21.49 (q); elemental analysis (%) for C17H19NO3S (317.40): calcd.: C 64.33,
H 6.03, N 4.41; found.: C 63.90, H 5.95, N 4.39.
K. P. C. Vollhardt, Synthesis 1994, 1374 ± 1382; c) D. B. Grotjahn in
Comprehensive Organometallic Chemistry II, Vol. 12 (Eds.: E. W.
Abel, F. G. A. Stone, G. Wilkinson), Pergamon, 1991, pp. 741 ± 770;
d) N. E. Shore in Comprehensive Organic Synthesis: Selectivity,
Strategy, and Efficiency in Modern Organic Chemistry, Vol. 5 (Eds.:
B. M. Trost, I. Fleming, L. A. Paquette), Pergamon, New York, 1991,
pp. 1129 ± 1162.
Received: March 23, 1999 [Z13202IE]
German version: Angew. Chem. 1999, 111, 2521 ± 2524
Keywords: alkynes
´ cyclotrimerizations ´ homogeneous
catalysis ´ indolines ´ rhodium
[9] B. Witulski, T. Stengel, Angew. Chem. 1998, 110, 495 ± 498; Angew.
Chem. Int. Ed. 1998, 37, 489 ± 492.
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Lett. 1993, 34, 23 ± 26; f) S. J. Neeson, P. J. Stevenson, Tetrahedron
1989, 45, 6239 ± 6248; g) R. Grigg, R. Scott, P. Stevenson, J. Chem. Soc.
Perkin Trans 1 1988, 1357 ± 1364; h) E. Müller, Synthesis 1974, 761 ±
774; i) J. P. Collman, J. W. Kang, W. F. Little, M. F. Sullivan, Inorg.
Chem. 1968, 7, 1298 ± 1303.
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1988, 27, 1113 ± 1126.
Â
[2] a) Ergot Alkaloids: Chemistry, Biological Effects (Eds.: Z. Rehacek, P.
Sajdl), Biotechnology, Elsevier, Amsterdam, 1990; b) D. C. Horwell,
Tetrahedron 1980, 36, 3123 ± 3149.
[3] a) K. Irie, K. Koshimizu, Comments Agric. Food Chem. 1993, 3, 1 ± 25;
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C. K. Chu, H. G. Cutler), Plenum, New York, 1992, pp. 257 ± 273.
[4] a) N. Lindquist, W. Fenical, G. D. Van Duyne, J. Clardy, J. Am. Chem.
Soc. 1991, 113, 2303 ± 2304.
[11] Amides
1 were synthesized by Mitsunobu reactions with the
corresponding alkynols and with N-BOC-p-toluenesulfonamide fol-
lowed by a deprotection reaction at 185 oC without solvent: J. R.
Henry, L. R. Marcin, M. C. McIntosh, P. M. Scola, G. D. Harris, Jr.,
S. M. Weinreb, Tetrahedron Lett. 1989, 30, 5709 ± 5712.
[5] K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter, G. M. L.
Patterson, S. Shaffer, C. D. Smith, T. A. Smitka, J. Am. Chem. Soc.
1994, 116, 9935 ± 9942.
[12] P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123 ± 1178; P. J.
Stang in Modern Acetylene Chemistry (Eds.: P. J. Stang, F. Diederich),
VCH, Weinheim, 1995, pp. 67 ± 98.
[13] 2,3-Dihydropyrroles originating from a 1,5-C-H insertion of alkyli-
dene carbenes formed in situ were not observed.[9] For additions of
nitrogen nucleophiles to alkynyliodonium salts and formation of 2,3-
dihydropyrroles see: a) K. S. Feldman, M. M. Bruendl, K. Schildknegt,
A. C. Bohnstedt, J. Org. Chem. 1996, 61, 5440 ± 5452; b) K. Schild-
knegt, A. C. Bohnstedt, K. S. Feldman, A. Sambandam, J. Am. Chem.
Soc. 1995, 117, 7544 ± 7545.
[6] A. P. Kozikowski, Heterocycles 1981, 16, 267 ± 291.
[7] a) K. Aoki, A. J. Peat, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120,
3068 ± 3073; b) D. L. Hughes, Org. Prep. Proced. Int. 1993, 25, 607 ±
632; c) J. H. Tidwell, S. L. Buchwald, J. Am. Chem. Soc. 1994, 116,
11797 ± 11810, and references therein.
[8] Reviews: a) H.-W. Frühauf, Chem. Rev. 1997, 97, 523 ± 596; b) M.
Lautens, Chem. Rev. 1996, 96, 49 ± 92; c) R. Boese, A. P. Van Sickle,
Angew. Chem. Int. Ed. 1999, 38, No. 16
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[14] All new compounds were characterized by 1H, 13C NMR, IR
spectroscopy, mass spectrometry, C,H,N analysis, and/or high-reso-
lution mass spectrometry.
[15] Grigg et al. suggested that polar solvents favor ligand dissociation and
thereby accelerate the catalysis.[10g] However, in the examples studied
by us, cyclotrimerizations occurred in toluene, which may be due to an
enhanced reactivity of the N-1-alkynylamides for cyclotrimerizations
in comparison with that of the diynes studied by Grigg.
tricyclopropylamine (3) appeared to be a particularly inter-
esting target for synthesis. In terms of the steric demand, a
cyclopropyl group is significantly smaller than an isopropyl
group[2] and slightly larger than an ethyl substituent, but is a
[16] Additional monosubstituted alkynes, such as phenyl acetylene and
1-pentyne, undergo cyclotrimerization reactions with the diynes 4a,
3i, and 3j. Further studies are in progress to explore the mechanistic
factors responsible for the selectivity, as well as cyclotrimerization
studies with nickel and cobalt catalysts.
[17] The structural assignment of compound 12a is based on 2D-NMR
experiments (H, H- and C, H-COSY, as well as HMBC) and distinct
NOE relationships. We would like to thank Prof. Dr. L Ernst
(Technische Universität Braunschweig) for the NOE measurements.
far better electron donor to adjacent electron-deficient
centers than any other alkyl group.[2, 3] Thus the three
cyclopropyl groups in 3 should stabilize its radical cation 3
.
‡
exceptionally well, so that the latter might be formed even
more readily than the radical cations of 1 and triethylamine
(2), just as the tricyclopropylmethyl cation emerges as a
particularly stable tertiary carbenium ion.[4] Since neither SN1
nor SN2 displacements on cyclopropyl derivatives are easily
achieved, 3 could not be prepared by straightforward cyclo-
propylation of cyclopropylamine. Fortunately, however, we
were able to develop a new general synthesis of cyclo-
propyldialkylamines from acid dialkylamides[5, 6] which was
readily adapted for the preparation of 3.[7]
Tricyclopropylamine and Its Radical Cation**
Armin de Meijere,* Vladimir Chaplinski, Harald
Winsel, Mikhael A. Kusnetsov, Paul Rademacher,
Roland Boese, Thomas Haumann, Marit Traetteberg,
Paul von R. Schleyer, Tosja Zywietz, Haijun Jiao,
Pascal Merstetter, and Fabian Gerson*
Dedicated to Professor George Olah
on the occasion of his 70th birthday
X-ray crystal structure analyses of tricyclopropylamine 3 at
130 K (Figure 1A)[9] and its hydrochloride at 200 K[11] re-
vealed that both have about the same pyramidal arrangement
In view of the report by Bock et al.[1] that triisopropylamine
(1) is nearly planar at the nitrogen atom, and can, therefore,
be oxidized unusually easily to a persistent radical cation,
[*] Prof. Dr. A. de Meijere, Dr. V. Chaplinski, Dipl.-Chem. H. Winsel,
Dr. M. A. Kusnetsov, Dipl.-Chem. T. Zywietz
Institut für Organische Chemie der Universität
Tammannstrasse 2, D-37077 Göttingen (Germany)
Fax: (‡49)551-39-9475
E-mail: ameijer1@uni-goettingen.de
Prof. Dr. F. Gerson, Dipl.-Chem. P. Merstetter
Institut für Physikalische Chemie der Universität Basel
Klingelbergstrasse 80, CH-4056 Basel (Switzerland)
Fax: (‡41)61-267-38-55
Figure 1. Structures of 3 in the crystal at 130 K (A)[9] and in the gas phase
(B).[14] The distances and angles given for crystalline 3 are mean values; the
interplanar angles between the plane C1,C4,C7 to the planes N,C1 and
center of C2 C3; N,C4 and center C5 C6; N,C7 and center C8 C9 are 97.5,
83.9, and 93.88, respectively. Shortest H ´´´ H distance 2.380(58) Š.
E-mail: gerson@ubaclu.unibas.ch
Prof. Dr. P. Rademacher
Institut für Organische Chemie der Universität-GH Essen (Germany)
Prof. Dr. R. Boese, Dr. T. Haumann
Institut für Anorganische Chemie der Universität-GH Essen (Ger-
many)
at the nitrogen atom (S(aC-N-C) ˆ 330.38). Moreover, the
orientation of all three cyclopropyl groups with respect to the
lone pair on the nitrogen atom in 3 and to the N H axis in 3 ´
HCl is exactly the same as that determined by computa-
tional[12, 13] and microwave-spectroscopic[13] studies on gas-
phase cyclopropylamine. A gas-phase electron diffraction
(GED) structure analysis of 3 established that the molecule in
the free state has essentially the same conformation (Fig-
ure 1B)[14] as in the crystal.
In this conformation, electron density can be delocalized
from the nitrogen lone pair into the symmetric components of
the cyclopropyl LUMOs.[12] In accord with the greater bulk of
the isopropyl compared to the cyclopropyl groups, the C N
bonds in 3 (1.446(1) Š) are shorter than those in 1 (GED:
1.460(5) Š[3], X-ray structure analysis at 84 K: 1.469(1) Š[15]),
Prof. Dr. M. Traetteberg
Department of Chemistry, NTNU ± Rosenborg
N-7491 Trondheim (Norway)
Prof. Dr. P. von R. Schleyer, Dr. H. Jiao
Center for Computational Quantum Chemistry
University of Georgia
Athens, GA 30602-2525 (USA)
[**] This work was supported by the Fonds der Chemischen Industrie, and
the Swiss National Science Foundation, as well as by BASF, Bayer,
Hoechst, and Degussa AG (chemicals). V.C. is indebted to the
Gottlieb Daimler and Karl Benz Stiftung for a graduate fellowship.
The authors are grateful to Prof. Jay Siegel, UC San Diego, as well as
Dr. Peter R. Schreiner, Göttingen, for fruitful discussions with respect
to the original manuscript, and Dr. B. Knieriem, Göttingen for his
careful proofreading of the manuscript.
2430
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