Synthesis of pyrroles from 1-dialkylamino-3-phosphoryl(or phosphanyl)allenes through 1,5-cyclization of conjugated azomethine ylide intermediates

Article abstract of DOI:10.1021/jo049586o

1-Dialkylamino-1,3-diaryl-3-diphenylphosphanylallenes 3a-e are thermally converted into a-annulated 3,5-diarylpyrroles 6a-f and [a]-annulated benzo[c]azepines 7a,b,d. These transformations are likely to include conjugated azomethine ylide intermediates that can undergo either a 1,5- or a 1,7-electrocyclization. The periselectivity is markedly shifted toward 1,5-cyclization when the diphenylphosphanyl substituent is replaced by the diphenylphosphoryl group. Thus, 1-dialkyl-amino-3-(diphenylphosphoryl)allenes 4a-f yield pyrroles 6 exclusively and with improved yields, unless the 3-aryl substituent in the allene is too electron-rich (e.g., benzodioxol-5-yl, 4f → 7f). The preparation and thermal transformation of aminoallenes 4 over three or four steps can be conducted as a one-pot procedure, thus providing a convenient synthesis of [a]-annulated 3,5-diarylpyrroles from enaminoketones.

Full text of DOI:10.1021/jo049586o

Syn th esis of P yr r oles fr om 1-Dia lk yla m in o-3-p h osp h or yl(or
p h osp h a n yl)a llen es th r ou gh 1,5-Cycliza tion of Con ju ga ted
Azom eth in e Ylid e In ter m ed ia tes
Martin Reisser and Gerhard Maas*
Division of Organic Chemistry I, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany
gerhard.maas@chemie.uni-ulm.de
Received March 12, 2004
1-Dialkylamino-1,3-diaryl-3-diphenylphosphanylallenes 3a -e are thermally converted into a-
annulated 3,5-diarylpyrroles 6a -f and [a]-annulated benzo[c]azepines 7a ,b,d . These transformations
are likely to include conjugated azomethine ylide intermediates that can undergo either a 1,5- or
a 1,7-electrocyclization. The periselectivity is markedly shifted toward 1,5-cyclization when the
diphenylphosphanyl substituent is replaced by the diphenylphosphoryl group. Thus, 1-dialkyl-
amino-3-(diphenylphosphoryl)allenes 4a -f yield pyrroles 6 exclusively and with improved yields,
unless the 3-aryl substituent in the allene is too electron-rich (e.g., benzodioxol-5-yl, 4f f 7f). The
preparation and thermal transformation of aminoallenes 4 over three or four steps can be conducted
as a one-pot procedure, thus providing a convenient synthesis of [a]-annulated 3,5-diarylpyrroles
from enaminoketones.
In tr od u ction
A mechanistically interesting approach to the pyrrole
ring system is the 1,5-electrocyclization of in-situ gener-
ated R,â-unsaturated nitrile ylides and azomethine ylides,8
representative examples of which are shown in Scheme
1. While the nitrile ylide system9 yields the pyrrole ring
directly, the azomethine ylide10 requires a subsequent
â-elimination to establish the conjugated π system; to this
end, vinamidinium10a and 3-chloropropene iminium
salts10b-f are well-suited starting materials which yield
the conjugated azomethine ylide after reaction with
N-alkylglycinates and deprotonation.
We have previously reported that 1-amino-3-vinyl-
allenes and 1-amino-3-(het)arylallenes undergo a thermal
isomerization to form dihydroazepine derivatives.11 The
mechanistic proposal for this transformation includes an
initial 1,4-H shift to form an R,â;γ,δ-conjugated azo-
methine ylide 1 which then undergoes an eight-electron
1,7-electrocyclic ring closure (Scheme 2). Numerous
examples of 1,7-electrocyclizations of R,â;γ,δ-unsaturated
1,3-dipoles are known,12 and the preferential 1,7- vs 1,5-
The pyrrole ring is probably the most important of the
five-membered heteroaromatic ring systems. Pyrrole
moieties are not only found in the porphine-type mol-
ecules of life but also in many other natural products of
plant or marine origin, and they form the backbone of
several important pharmaceuticals and agrochemicals.
Therefore, it is not surprising that the wide array of
established and practical pyrrole syntheses1 is continu-
ously supplemented by novel methods to prepare substi-
tuted and functionalized pyrroles, in particular those that
are not readily available by the classical approaches.
Novel recent pyrrole syntheses include the reductive ring
contraction of pyridazines,2 the Cu(I)-assisted 1,5-cycliza-
tion of alkynyl imines,3 the palladium-catalyzed cycliza-
tion of R-propargyl-â-iminophosphanoxides,4 cyclization
of 4-aminobut-2-en-1-ones5 and 4-amino-3-hydroxy-
ketones,6 and cyclization of δ-enaminoesters with N-
bromosuccinimide.7
* Corresponding author. Fax: +49 731-50-22803.
(7) Agami, C.; Dechoux, L.; Hebbe, S. Synthesis 2001, 1440-1442.
(8) Review: Huisgen, R. Angew. Chem. 1980, 92, 979-1005.
(9) Padwa, A.; Smolanoff, J .; Tremper A. J . Am. Chem. Soc. 1975,
97, 4682-4691.
(1) Black, D. StC. In Science of Synthesis; Maas, G., Ed.; Thieme:
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Methoden der organischen Chemie; Kreher, R., Ed.; Thieme: Stuttgart
1994; Vol. E6a/1, pp 556-798. Sundberg, R. J . In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: New York 1994; Vol. 2, p 119. J ones, R. A. In
The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley &
Sons: New York 1990; Vol. 48, Part 1, .
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W.; Sikorski, J . A. J . Org. Chem. 1990, 55, 4735-4740. (b) Gupton, J .
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J ones, C. R. J . Org. Chem. 1992, 57, 5480-5483. (c) Gupton, J . T.;
Hicks, F. A.; Wilkinson, D. R.; Petrich, S. A. Heterocycles 1994, 37,
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R.; Vargas, M.; Hosein, K. N.; Sikorski, J . A. Heterocycles 1998, 47,
689-702. (e) Gupton, J . T.; Petrich, S. A.; Smith, L. L.; Bruce, M. A.;
Vu, P.; Du, K. X.; Dueno, E. E.; J ones, C. R.; Sikorski, J . A. Tetrahedron
1996, 52, 6879-6892. (f) Gupton, J . T.; Krumpe, K. E.; Burnham, B.
S.; Dwornik, K. A.; Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.;
Vargas, M.; Keertikar, K. M.; Hosein, K. N.; J ones, C. R.; Sikorski, J .
A. Tetrahedron 1998, 54, 5075-5088.
(2) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; J in, Q.
J . Am. Chem. Soc. 1998, 120, 12147-.
(3) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J . Am. Chem.
Soc. 2001, 123, 2074-2075. (b) Rubin, M.; Sromek, A. W.; Gevorgyan,
V. Synlett 2003, 2265-2291.
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(b) Reinhard, R.; Glaser, M.; Neumann, R.; Maas, G. J . Org. Chem.
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10.1021/jo049586o CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/19/2004
J . Org. Chem. 2004, 69, 4913-4924
4913

Reisser and Maas
SCHEME 1
SCHEME 3
SCHEME 2
cyclization of these entities has been adressed by several
authors.13 Nevertheless, we wondered why we never
observed products resulting from the 1,5-cyclization of
azomethine ylides 1, in particular in those cases where
the 1,7-cyclization required the temporary loss of aro-
maticity of the involved (het)aryl ring.
We report now that the nature of substituent R in
Scheme 2 has a decisive influence on the periselectivity
of the electrocyclic ring closure of azomethine ylide
intermediates 1: while we had observed only 1,7-elec-
trocyclization when R was a phenyl, 2-furyl, 2-thienyl,
t-Bu, or SiPh2-t-Bu substituent,11 1,5-electrocyclization
becomes a competitive or the dominant pathway when
R is a phosphanyl or phosphoryl group.
phosphane or O-trimethylsilyl diphenylphosphinite, re-
spectively (Scheme 3). When allene 3a was heated in
toluene at 120-140 °C in a closed Schlenk tube, a
complex product mixture was obtained. The 31P NMR
spectrum showed the presence of three major phosphorus-
containing products: while the signal at δ ) -41 ppm
was attributed to HPPh2 and the signal at δ 0.6 could
later be assigned to the expected oxazino[4,3-a]azepine
derivative 5a , the origin of a peak at δ -13.9 remained
unclear. The proton NMR spectrum of the crude mixture,
after flash chromatography over silica gel, also indicated
the formation of pyrrolo[2,1-c][1,4]oxazine 6a .15 Unfor-
tunately, compounds 5a and 6a have very similar Rf
values so that a straightforward chromatographic sepa-
ration was not possible and only a small amount of pure
azepine derivative 5a could be isolated by preparative
thick-layer chromatography. On the other hand, treat-
ment of the crude mixture of 5a and 6a with aqueous
hydrogen peroxide converted 5a into phosphanoxide 7a ,
and the mixture of 6a and 7a was readily separated by
column chromatography. However, the isolated yields
(12% each of 6a and 7a ) no longer agree with the initial
product ratio where the azepine derivative dominated
over the bicyclic pyrrole.
Resu lts a n d Discu ssion
We began our thermal isomerization studies with
phosphorus-substituted aminoallenes 3a and 4a , which
were prepared, as we have reported recently,14 from
propyne iminium triflate 2a and diphenyl(trimethylsilyl)-
(12) Reviews: (a) Zecchi, G. Synthesis 1991, 181-188. (b) Ground-
water, P. W.; Nyerges, M. Adv. Heterocycl. Chem. 1999, 73, 97-129.
(13) (a) Cullen, K. E.; Sharp, J . T. J . Chem. Soc., Perkin Trans. 1
1995, 2565-2579. (b) Marx, K.; Eberbach, W. Chem. Eur. J . 2000, 6,
2063-2068. (c) Friebolin, W.; Eberbach, W. Helv. Chim. Acta 2001,
84, 3822-3836. (d) ref 12b.
(15) A diagnostic test for the presence of this and all other pyrroles
reported in this study was provided by the strong fluorescence on a
TLC plate upon irradiation with 366 nm light.
(14) Reisser, M.; Maier, A.; Maas, G. Eur. J . Org. Chem. 2003, 2071-
2079.
4914 J . Org. Chem., Vol. 69, No. 15, 2004

Pyrroles from 1-Dialkylamino-3-phosphorylallenes
SCHEME 4 a
CHART 1. P r op yn e Im in iu m Sa lts P r ep a r ed in
Th is Stu d y
a
Conditions: (a) ArCOCl, AlCl3, CH2Cl2, 0 °C, 55-80%; (b) (1)
Tf2O, CH2Cl2, -78 f 0 °C, (2) remove solvent, then 180-200 °C/
0.001 mbar/15 min (2b,c,e); or NEt-i-Pr2, CH2Cl2, -78 f 0 °C
(2d ,f-j); (c) (1) Me3Si-PPh2, anhyd LiCl, THF, -78 f +20 °C,
(2) remove volatiles, extract allene into toluene; (d) (1) Me3SiO-
PPh2, LiCl, THF, -78 f +20 °C, (2) remove volatiles, add toluene.
See Table 1 and Scheme 5 for substituents
Diphenylphosphoryl-substituted morpholinoallene 4a
undergoes the thermal reaction much more readily than
3a . The allene was almost completely consumed after 1
h when kept in toluene at 100 °C. The chromatographic
workup furnished pyrrole 6a (24% yield) and only trace
amounts of oxazinoazepine derivative 7a ; the formation
of diphenylphosphanoxide (δ(31P) 22.9) and of several
1
minor byproducts was indicated by the H and 31P NMR
spectra. Among these products are the inevitable prod-
ucts of hydrolysis of the extremely moisture-sensitive
allene 4a .
To explore the substituent effects on the rate and
periselectivity of the thermal transformations, several
other 3-phosphorus-substituted aminoallenes were pre-
pared. The synthetic plan followed our established pro-
cedure16,17 by which enaminoketones 9, readily obtained
from propynones 8, were O-sulfonylated with triflic
anhydride and the resulting 3-trifloxypropene iminium
triflates were converted into propyne iminium triflates
2 by thermal or NEt-i-Pr2-assisted elimination of triflic
acid (Scheme 4).
The thermal elimination (180-200 °C/0.001 mbar) was
suited to prepare salts 2b,c,e (Chart 1) but could not be
used in other cases because of the acid sensitivity of
substituents or nonselective reactions. In these cases, the
generally applicable base-assisted elimination procedure
was applied which gave an equimolar mixture of the
corresponding propyne iminium triflate 2d ,f-j and di-
isopropylethylammonium triflate that could be used for
the synthesis of allenes 3 and 4.
was not possible. However, the crude allenes could be
subjected to thermal reactions without complication.
Allene 3e is thermally labile even at 20 °C; in solution it
was completely consumed within 1 day, yielding pyrrole
6e as the only heterocyclic product. All allenes were
unequivocally identified by their 1H and 13C NMR
spectra; in particular, the 13C resonance of the central
allenic carbon atom (δ ) 205.1-206.5 ppm) is diagnostic.
The 3-diphenylphosphoryl-substituted aminoallenes
4b-g were prepared by reaction of propyne iminium salts
2f-g with O-trimethylsilyl diphenylphosphinite (Scheme
4). In almost all cases, the attack of the phosphorus
nucleophile at the conjugated iminium salt is regiospe-
cific, except for salt 2d which also gave a small amount
of (1-piperazinopropargyl)diphenylphosphanoxide 10. None
of the allenes 4b-g was isolated because of their antici-
pated14 moisture sensitivity; rather, the crude product
mixtures, after replacing THF by toluene as solvent, were
directly subjected to the thermal transformations. The
benzylamino-substituted allenes 4e,g underwent further
thermal reaction even faster than allene 2e mentioned
above: at ambient temperature, this transformation is
so fast that these allenes could not be detected by NMR
spectroscopy.
Reaction of salts 2b-e with diphenyl(trimethylsilyl)-
phosphane provided the expected diphenylphosphanyl-
substituted allenes 3b-e in high yields. Allenes 3b-d
are thermally stable at 20 °C but are very moisture-
sensitive so that purification, including the complete
separation from lithium triflate formed as a byproduct,
The thermally induced transformations of allenes
3b-e and 4b-f are summarized in Table 1. For 3b-d ,
(16) Singer, B.; Maas, G. Chem. Ber. 1987, 120, 485-495.
(17) Rahm, R.; Maas, G. Synthesis 1994, 295-299.
J . Org. Chem, Vol. 69, No. 15, 2004 4915

Reisser and Maas
TABLE 1. Th er m a lly In d u ced Tr a n sfor m a tion s of 1-Am in o-3-(d ip h en ylp h osp h a n yl)a llen es 3b-e a n d
1-Am in o-3-(d ip h en ylp h osp h or yl)a llen es 4b-f
a
Repeated recrystallization to remove impurities caused material loss in several cases, explaining some of the low yields reported
b
here. The crude product mixture was treated with 1% aqueous H2O2 before chromatographic workup. The following ratios of pyrrole 6
1
and PPh2-substituted azepine derivative 5 were determined by H NMR before oxidation and workup: 5b/6b ) 1.5; only 6c from 3c; only
6e from 3e; 5d /6d ) 0.48. c The allene was not isolated (see text); the yield of the product(s) refers to the corresponding iminium salt 2.
d
Propargylamine 10 was also formed (8% based on iminium salt 2d ).
4916 J . Org. Chem., Vol. 69, No. 15, 2004

Pyrroles from 1-Dialkylamino-3-phosphorylallenes
SCHEME 5 a
DMF was chosen as the reaction medium because this
did not require conducting the reaction at a temperature
far beyond its boiling point as would have been the case
with toluene; it was tested, however, that the results in
DMF or toluene solution were similar. It can be seen that
in some cases mixtures of pyrroles 6 and azepine deriva-
tives 7 were obtained while in other cases the pyrrole
was the only product found. Starting with allenes 3b,d ,
it was again necessary to oxidatively convert the PPh2-
substituted azepine derivatives into phosphanoxides 7b,d
in order to achieve the chromatographic separation of 6
and 7. The isolated yields given in Table 1 do not always
reflect the true yields, not even the original ratios of 1,5-
vs 1,7-cyclization product, because of material loss during
workup or purification. Nevertheless, including the re-
sults discussed above for 3a and 4a , the following general
observations can be made: None of the PPh2-substituted
aminoallenes 3a -e reacts cleanly, and the heterocyclic
products are isolated only in low yields. In contrast, a
P(O)Ph2 substituent at the C-3 terminus of the allenes
(4a -g) accelerates the reaction significantly and yields
the corresponding pyrrole with much better selectivity
and generally in markedly enhanced yield. The best
pyrrole yields were obtained with those aminoallenes that
in addition to the P(O)Ph2 group bear an acceptor-
substituted phenyl ring at the C-3 terminus (4b,c) while
the benzodioxol-5-yl substituent in 4f clearly favors
formation of the seven-membered ring system 7f. It is
also worth being noted that the mildness of the thermal
transformation, which is observed whenever the ami-
noallene contains a benzylamino moiety (reactions occur
at e20 °C), does not guarantee a clean transformation
into pyrroles 6 or azepine derivatives 7. This suggests
that the significant loss of material in the majority of
these reactions, the reason of which remains unknown
so far, is not a consequence of the elevated reaction
temperatures.
It should be noted that a-annulated benzazepine
derivatives 5 and 7 have two stereogenic centers but only
one diastereomer was obtained. The trans configuration
1
was derived from the similarity of the relevant H NMR
data with those of closely related systems the structure
of which was established by X-ray structure determi-
nation.11a,18,19 This configuration is in agreement with a
conrotatory 8π electrocyclization mode of azomethine
ylide intermediates 1 (Scheme 2) followed by a supra-
facial [1,5]-H shift.
a
Conditions: (a) Tf2O (1 equiv), CH2Cl2, -78 f +20 °C, 45 min;
Having established some directions for a selective
pyrrole synthesis, we explored the possibility of making
the four-step conversion of enaminoketones 9 into pyr-
roles 6 more convenient. In fact, we found that the four-
step reaction sequence could be conducted as a one-pot
procedure without isolation of any reaction intermediate.
Thus, successive treatment of an enaminoketone with
triflic anhydride, diisopropylethylamine, and (Me3SiO)-
PPh2/LiCl at low temperature, followed by the thermal
conversion of the allene, gave pyrroles 6e,g-k (Scheme
5). The procedure becomes essentially a three-step pro-
(b) NEt-i-Pr2 (1 equiv), -78 f 0 °C, 30 min; (c) Me3SiO-PPh2 (1
equiv), anhyd LiCl (1 equiv), -78 f +20 °C, 12 h; (d) toluene, 100
°C, 12 h.
cess for N-benzyl enaminoketones 6e,g,k because the
allene-to-pyrrole conversion occurs already at 20 °C and
does not require a change of solvent. The one-pot proce-
dure also allows a reasonable scale-up; thus, the conver-
sion (E,Z)-9h f 6h was performed without a problem on
a 0.12 M scale.
The examples given in Scheme 5 provide further
information on the scope of the novel pyrrole synthesis:
(a) The exclusive formation of pyrrole 6g from enami-
noketone 9g contrasts with the predominant dihy-
droazepine formation from allene 4f (see Table 1). This
suggests that the lower reaction temperature in the case
of N-benzyl enaminoketones (or aminoallenes) is suf-
(18) Maas, G.; Manz, B.; Mayer, T.; Werz, U. Tetrahedron 1999, 55,
1309-1320.
(19) In particular, the H,H coupling constants indicate that the
angular hydrogen 12b-H occupies an equatorial position at the chairlike
morpholine or piperazine ring. In the NOESY spectrum, 12b-H shows
a weak correlation peak with 7-H but not with 6-H.
J . Org. Chem, Vol. 69, No. 15, 2004 4917

Reisser and Maas
SCHEME 6
ficient to override the unfavorable influence of the
electron-rich benzodioxolyl substituent on the 1,5-cycliza-
tion. (b) For enaminoketone 9j, the ester group at C-3 of
the piperidine ring controls the regioselectivity of the ring
closure only to a limited extent. The preferential forma-
tion of 6jB may be due to steric reasons, assuming an
equilibrium between the two possible azomethine ylide
intermediates. An electronic effect is also conceivable: if
the initial [1,4]-H shift, which converts 9j into an azome-
thine ylide, is hydridic in nature (vide infra), the develop-
ing positive charge on the carbon atom adjacent to N is
slightly better stabilized at C-6 rather than C-2 of the
piperidine-3-carboxylate. This example also shows that
the presence of the ester group is compatible with the
use of triflic anhydride as a reagent and the intermediate
formation of a trifloxypropene iminium salt; in contrast,
3-trifloxypropene iminium salts derived from 2-dialkyl-
amino-4-oxobutenoates underwent cylization to form
iminium-substituted ∆2,3-butenolides.20
Further variations of the reaction conditions for the
pyrrole synthesis provided the following results: The use
of O-trimethylsilyl bis(4-fluorophenyl)phosphonite (A) or
O-trimethylsilyl bis(4-chlorophenyl)phosphonite (B) in-
stead of Me3SiO-PPh2 appears to improve the yield of
pyrrole (one-pot procedure from enaminoketone: 33% of
6a using A, 14% of 6f with A, 76% of 6d with B), but a
systematic comparison was not made. On the other hand,
Me3SiO-PPh2 cannot generally be replaced by the phos-
phite Me3SiO-P(OEt)2 which tends to react with propyne
iminium salts to give propargylphosphonates rather than
allenylphosphonates.14 Because of the same regioselec-
tivity problem, N-aryl-N-alkyl enaminoketones are less
efficiently converted into pyrroles using the procedure
shown in Scheme 5.
Under the aspect of synthetic methodology, it is evident
that the conversion of enaminoketones 9 into pyrroles 6
is a simple intramolecular cyclocondensation reaction
with elimination of a water molecule. The procedure
developed here solves the problem that the NCH2 protons
of the enaminoketones are not mobile enough to get the
cyclocondensation going. In this context, the following
observation21 deserves being mentioned: The reaction of
dibenzoylmethane and pyrrolidine in benzene and in the
presence of molecular sieves yields either the expected
enaminoketone or 5,7-diphenyl-2,3-dihydro-1H-pyrroliz-
ine, depending on the reaction conditions. It is not clear
whether the latter product results from a cycloconden-
sation of the enaminoketone and if so, what the exact
mechanism is. To our knowledge, a generalization of this
finding has not been reported.
2-vinyl-N,N-dialkylanilines.22 Thus, the P(O)Ph2 sub-
stituent renders the central allenic carbon more electron-
deficient, and the resulting conjugated azomethine ylide
is stabilized in the 1,5-dipolar form 11, relative to
resonance structure 1, by a phenyl substituent at the
iminium carbon atom C-1 and the electron-accepting
P(O)Ph2 substituent at C-5 (Scheme 6). The observation
that the N-benzyl-substituted aminoallenes 3e, 4e as well
as those derived from 9e and 9k (Scheme 5, allenes not
shown) undergo thermal conversion already at 20 °C,
while all other aminoallenes investigated in this study
require much more forcing conditions, indicates that at
least in these latter cases the initial [1,4]-H shift is the
rate-limiting step; furthermore, it is obvious that all
subsequent steps of pyrrole formation (cyclization of the
azomethine ylide intermediate, elimination of HPPh2 or
HP(O)Ph2 from the dihydropyrrole) occur already at room
temperature.23
A discussion of the factors governing the periselectivity
of the azomethine ylide cyclization (1,5- vs 1,7-cyclization)
remains speculative at present, above all because the true
yields (i.e., before workup) of pyrroles 6 and azepine
derivatives 5 and 7 are not known. Inspection of litera-
ture studies on related conjugated dipoles (see the
Introduction) leaves us with the impression that several
different factors may be in operation the relative impor-
tance of which changes from one particular system to the
Mech a n istic Aspects. A general outline of the mecha-
nistic scenario has been given in the Introduction. As
shown in Scheme 2, our previous investigations have
suggested that the initial [1,4]-H shift, although probably
a concerted process, corresponds to a proton migration
to the electron-rich central allenic carbon atom. On the
other hand, the rate-accelerating effects of the phosphoryl
and N-benzyl substituents in aminoallenes 4 indicate
that the [1,4]-H shift is more favorable if it has a hydridic
character, similar to thermal isomerization reactions of
(22) (a) Reinhoudt, D. N.; Verboom, W.; Visser, G. W.; Trompenaars,
W. P.; Harkema, S.; van Hummel, G. J . J . Am. Chem. Soc. 1984, 106,
1341-1350. (b) Verboom, W.; Reinhoudt, D. N. Recl. Trav. Chim. Pays-
Bas 1990, 109, 311-324.
(23) A reviewer has suggested
a competitive pathway for the
conversion of aminoallenes 3,4 into pyrroles 6, which includes 3-P(X)-
Ph2-substituted propene iminium salts being formed by C2-protonation
of the aminoallenes. Preliminary experiments have shown that, e.g.,
the C2-protonated aminoallene 4a is converted into pyrrole 6a at much
harsher conditions (NEtiPr2, CH3CN, 140 °C, 12 h) and in lower yield
than aminoallene 4a itself. This suggests that the thermal conversion
of aminoallenes 4 reported in this study does not proceed via their
C-protonated form.
(20) Nikolai, J .; Maas, G. Synthesis 2003, 2679-2688.
(21) Soeder, R. W.; Bowers, K.; Pegram, L. D.; Cartaya-Marin, C.
P. Synth. Commun. 1992, 33, 2737-2740.
4918 J . Org. Chem., Vol. 69, No. 15, 2004

Pyrroles from 1-Dialkylamino-3-phosphorylallenes
SCHEME 7
SCHEME 8
other. The cyclization step could be orbital- or charge-
controlled (i.e., a “true” 6π vs 8π electrocyclization or a
1,5- vs 1,7-dipolar cyclization8). Calculations by Eberbach
and Marx for butadienyl-substituted pyridinium ylides13c
support the view that the orbital-controlled mode favors
the 1,7-cyclization, because the helical transition-state
geometry is particularly suited for a conrotatory 8π
cyclization. On the other hand, a 1,5-dipolar bond struc-
ture such as 11 may be stabilized by appropriate sub-
stituents, and we consider it likely that formation of
pyrroles 6 from the 3-phosphanyl- and 3-phosphoryl-
substituted aminoallenes is due to a charge-controlled
pathway. Furthermore, it has occasionally been specu-
lated that the absence of 1,5-cyclization products may
also be due to the reversibility of dihydropyrrole (12)
formation. If this was the case, one could argue that the
fast â-elimination of HPPh2 or HP(O)Ph2 renders dihy-
dropyrrole formation irreversible and therefore supports
the 1,5-cyclization mode. However, the isolation of dihy-
dropyrroles in cases where P(O)Ph2 was replaced by
than 6d , which is presumably the 1-oxo derivative of 6d ,
was not isolated. While 14 turned out to be stable and
could be fully characterized by spectroscopy and elemen-
tal analysis, the air-sensitive desoxy analogue 13 could
not be obtained in analytically pure form. The 1H and
13C NMR data of 14 fully agree with the proposed
structure; among other things, the observation of an
ABMN spin system for the NCH2CH2 protons indicates
the presence of a neighboring stereogenic center. The
NMR spectra of 13 are quite similar to those of 14, except
for the changes caused by the absence of the OH sub-
stituent. However, an unexpected difference was found
for the chemical shifts of the Nformamide-CH2 group
(13: δH ) 3.73, 4.14, δC ) 43.1; 14: δH ) 3.32, 4.74, δC )
46.3), while the chemical shifts for the Npyrrole-CH2 group
are very similar. This suggests that either the conforma-
tions at the NCCN bonds or the configuration at the
N-CHO bond are different, perhaps due to the presence
of an intramolecular O-H‚‚‚O hydrogen bond in 14. It
should be mentioned that oxidation reactions of pyrroles
are known to be complex;26 a 5-hydroxypyrrolin-2-one
similar to 14 was obtained by air oxidation of 2,4-
dimethylpyrrole.27
24
SiMe3 shows that the 1,5-cyclization can compete with
the 1,7-cyclization mode also in cases where the 1,5-cycli-
zation is not triggered by a subsequent elimination step.
F u r th er Tr a n sfor m a tion s of P yr r oles 6d a n d 6h .
Pyrrole 6d features the 1,2,3,4-tetrahydropyrrolo[1,2-a]-
pyrazine skeleton which is found in several compounds
of considerable pharmacological interest.25 Notably, 6d
was found to be extremely sensitive to aerial oxidation,
in contrast to all other pyrroles synthesized in this study.
It was therefore necessary to perform the chromato-
graphic separation of 6d under an inert atmosphere.
When solid 6d was exposed to air for 2 weeks, it
underwent complete oxidative degradation to a complex
mixture of products. According to mass spectrometry, the
major constituents of the mixture had molecular masses
which were by 14, 32, and 48 units higher than that of
6d . Complete chromatographic separation of the mixture
was not possible due to similar Rf values and the
instability of some of the components. At least, a small
amount of two compounds could be obtained to which
structures 13 and 14 were assigned (Scheme 7) which
correspond to the incorporation of two and three oxygen
atoms, respectively. A product with 14 mass units higher
Another transformation of pyrrole 6d was found when
the synthesis from propyne iminium salt 2d was at-
tempted in the presence of 2 equiv rather than 1 equiv
of Me3SiO-PPh2 (Scheme 8). Formanilide 15 was isolated
as the only product in 33% yield which obviously results
from a nucleophilic attack at the pyrrolyl-CH2 position
of 6d and ring-opening.
The pyrrole synthesis presented in this work yields
1,2,3,5-tetrasubstituted pyrroles with a low degree of
functionalization. With a view to further synthetic elabo-
ration, we show here as an example how additional
functional groups can be introduced into 6h (Scheme 9).
First, position C-4 of the pyrrole ring should be amenable
to electrophilic halogenation. In fact, bromination with
NBS/AlBr3 provided bromopyrrole 16 in acceptable yield.
Notably, attempts to achieve bromination with CuBr2 and
iodination with I2/K2CO3/MeOH or ICl met with failure,
probably because of steric shielding of the C-4 position
by the adjacent aryl rings. The acylation of the pyrrole
ring using acetyl chloride, oxalyl chloride or acetic
anhydride in the presence of AlCl3 or pyridine was also
unsuccessful, probably for the same reason. On the other
hand, a polar functional group was readily introduced
(24) J . Schlegel, Doctoral Thesis, University of Ulm, 1999.
(25) See, for example: (a) Branca, Q.; J akob-Røtne, R.; Kettler, R.;
Ro¨ver, S.; Scalone, M. Chimia 1995, 49, 381-385. (b) Katritzky, A.
R.; J ain, R.; Xu, Y.-J .; Steel, P. J . J . Org. Chem. 2002, 67, 8220-8223.
(c) Wyss, P. C.; Gerber, P.; Hartman, P. G.; Hubschwerlen, C.; Locher,
H.; Marty, H.-P.; Stahl, M. J . Med. Chem. 2003, 46, 2304-2312 and
references cited therein.
(26) Gardini, G. P. Adv. Heterocycl. Chem. 1973, 15, 67-98.
(27) Ho¨ft, E.; Katritzky, A. R.; Nesbit, M. R. Tetrahedron Lett. 1967,
3041-3044; 1968, 2028.
J . Org. Chem, Vol. 69, No. 15, 2004 4919

Reisser and Maas
SCHEME 9 a
evolution of triflic acid was over (15 min). The black residue
was allowed to cool and then dissolved in a minimum amount
of CH3CN, and ether was added until the solution became
turbid. After 24 h at -30 °C, some product had crystallized.
An also separated black oil was removed with
a pipet.
Additional batches of product were obtained by addition of
more ether and repeating this procedure. Analytically pure
salt 2b was obtained after at least two recrystallizations from
acetonitrile-ether: yield 11.55 g (44%) of a light-brown
microcrystalline powder; mp 128 °C; IR (KBr) 2191 (vs), 1592
(s), 1264 (vs), 1030 (s), 636 (s) cm-1; 1H NMR (500.14 MHz) δ
3.91 (pseudo-t, 2H), 4.17 (pseudo-t, 2H), 4.25 (pseudo-t, 2H),
4.67 (pseudo-t, 2H), 7.15 (mc, 2H), 7.54-7.86 (m, 7H); 13C NMR
(125.77 MHz) δ ) 54.0, 56.5, 66.1, 66.3, 83.8, 114.3 (d, J ∼ 5
Hz), 116.6 (d, J C,F ) 22.6 Hz), 120.6, 129.2, 129.5, 130.0, 133.7,
135.5 (d, J C,F ) 9.5 Hz), 162.0, 165.4 (d, J C,F ) 258.4 Hz). Anal.
Calcd for C20H17F4NO4S (443.41): C, 54.17; H, 3.86, N, 3.16.
Found: C, 53.97; H, 3.64; N, 3.07.
a
Conditions: (a) NBS, AlBr3 (10 mol %), CH2Cl2, -78 f +20
°C, 57%; (b) (1) Mg, THF, 100 °C, 12 h, (2) CO2, (3) 5% aq HCl;
63% yield.
4-[3-(3,4-Dich lor op h en yl)-1-p h en yl-2-p r op yn ylid en e]-
m or p h olin iu m Tr iflu or om eth a n esu lfon a te (2c). Follow-
ing the procedure described for 2b, triflic anhydride (11.84 g,
0.042 mol) was combined with enaminoketone 9c (14.50 g,
0.040 mol) in CH2Cl2 (300 mL). The formed salt, [3-(3,4-
dichlorophenyl)-1-phenyl-3-(trifluoromethylsulfonyl)oxy-2-pro-
penylidene]morpholinium triflate, was kept in a rotating
Kugelrohr apparatus at 200 °C/0.001 mbar until evolution of
triflic acid had ceased. The residual product was recrystallized
twice from a mixture of CH3CN (30 mL) and ether (40 mL) to
give a light-brown solid (9.55 g, 48%): mp 166 °C; IR (KBr)
by the conversion of the bromophenyl into a benzoic acid
moiety (6h f 17).
Con clu sion
The introduction of a PPh2 or, even better, a P(O)Ph2
substituent at the C-3 position of 1-dialkylamino-1,3-
diarylallenes has allowed us, for the first time, to achieve
the thermal conversion of these allenes into pyrroles. In
mechanistic terms, these substituents favor the 1,5- over
the 1,7-electrocyclization of R,â:γ,δ-unsaturated azome-
thine ylide intermediates which are generated by a
thermal [1,4]-H shift from the aminoallenes. While the
full scope of the new pyrrole synthesis remains to be ex-
plored, the present results indicate that it is particularly
suited to prepare 3,5-diarylpyrroles that are [a]-annu-
lated with five- or six-membered rings, e.g., of compounds
with the pyrrolizidine, indolizidine, and pyrrolo[1,2-a]-
pyrazine ring skeleton. Furthermore, the aminoallene-
to-pyrrole transformation can be applied to convert N,N-
dialkylenaminoketones into pyrroles through a formal
1,5-cyclocondensation of the CH2NCdCCdO unit. The
required three- or four-step sequence can be performed
conveniently without isolation of any intermediate
product.
2206 (s), 1603 (w), 1273 (s), 1255 (vs), 1028 (vs), 637 (s) cm-1
;
1H NMR (400.13 MHz) δ 3.90 (pseudo-t, 2H), 4.13 (pseudo-t,
2H), 4.21 (pseudo-t, 2H), 4.64 (pseudo-t, 2H), 7.45-7.85 (m,
8H); 13C NMR (100.61 MHz) δ 54.5, 57.2, 66.3, 66.5, 84.5, 118.1,
118.1, 129.3, 129.8, 130.2, 131.3, 132.7, 133.7, 133.9, 134.7,
138.3, 162.4. Anal. Calcd for C20H16Cl2F3NO4S (494.31): C,
48.60; H, 3.26; N, 2.83. Found: C, 48.53; H, 3.16; N, 2.84.
2-(1,3-Diph en yl-2-pr opyn yliden e)-2,3-dih ydr o-1H-isoin -
d oliu m Tr iflu or om eth a n esu lfon a te (2e). Prepared as de-
scribed for 2c, from enaminoketone 9e (11.50 g, 0.035 mol)
and triflic anhydride (10.30 g, 0.036 mol): rose-colored solid;
yield 8.82 g (55%); mp 192 °C; IR (KBr) 2200 (vs), 1556 (s),
1
1377 (s), 1268 (vs), 1150 (s), 1032 (vs), 638 (s) cm-1; H NMR
(500.14 MHz) δ 5.45 (s, 2H), 5.79 (s, 2H), 7.10-8.05 (m, 14H);
13C NMR (125.77 MHz) δ 60.5, 63.4, 84.6, 117.6, 120.1, 122.3,
122.6, 128.6, 129.0, 129.46, 129.53, 130.3, 131.5, 132.6, 133.4,
133.8, 134.5, 160.5. Anal. Calcd for C24H18F3NO3S (457.47): C,
63.01; H, 3.96; N, 3.06. Found: C, 63.08; H, 4.22; N, 3.03.
Syn th esis of P r op yn e Im in iu m Tr ifla tes 2d ,f-j in
Solu tion (Gen er a l P r oced u r e). Triflic anhydride (1.48 g,
5.25 mmol) was placed in a round-bottom flask that had been
dried with a heat gun and flushed with argon. Anhydrous
CH2Cl2 (20 mL) was added, and the solution was cooled at -78
°C in an acetone/dry ice bath. A solution of an enaminoketone
9 (5 mmol) in CH2Cl2 (20 mL) was added dropwise. The cooling
bath was removed, and the solution was allowed to assume a
temperature of 0 °C within 15 min (formation of a 3-triflox-
ypropene iminium salt). After cooling again at -78 °C,
diisopropylethylamine (0.87 mL, 0.646 g, 5.0 mmol) was added,
and the solution was brought to 0 °C within 15 min, thereby
assuming an orange or light-brown color. This solution of
propyne iminium triflate 3 and diisopropylethylammonium
triflate was used for further reactions. According to 1H NMR,
the formation of 3 was virtually quantitative.
Exp er im en ta l Section
Diphenyl(trimethylsilyl)phosphane28 (Me3SiPPh2) and O-
trimethylsilyl diphenylphosphinite29 (Me3SiOPPh2) were pre-
pared by published procedures. Anhydrous lithium chloride
was obtained by heating at 150 °C/0.04 mbar for 2 h.
4-[3-(4-F lu or op h en yl)-1-p h en yl-2-p r op yn ylid en e]m or -
p h olin iu m Tr iflu or om eth a n esu lfon a te (2b). A solution of
triflic anhydride (17.00 g, 0.060 mol) in CH2Cl2 (350 mL) was
cooled at -78 °C, and solid enaminoketone 9b (18.50 g, 0.059
mol) was added portionwise under an argon atmosphere. The
solution was brought to 20 °C during 2 h and concentrated to
half of its volume, and anhydrous ether was added in order to
precipitate the formed product, [3-(4-fluorophenyl)-1-phenyl-
3-(trifluoromethylsulfonyl)oxy-2-propenylidene]morpholini-
um triflate. The precipitate was isolated by filtration under
an argon atmosphere and washed with anhydrous ether until
the crystalline solid was almost colorless. It was then briefly
kept at 0.01 mbar to remove residual solvent and was kept in
a rotating Kugelrohr apparatus at 180 °C/0.001 mbar until
After removal of the solvent, salts 2b-j were obtained in
admixture with diisopropylethylammonium triflate and were
characterized by the following spectroscopic data: IR ν(CtC)
2179-2206 cm-1
;
13C NMR δ 83.4-89.3 (C≡CCdN+), δ 153.8-
163.5 (CdN+).
Salt 2d was exemplarily separated from the ammonium
salt byproduct as follows. Anhydrous ether was added to the
CH2Cl2 solution until precipitation began. The precipitate was
collected, and the colorless crystals of the ammonium salt were
(28) Appel, R.; Geisler, K. J . Organomet. Chem. 1978, 112, 61-64.
(29) (a) Issleib, K.; Walther, B. Angew. Chem., Int. Ed. Engl. 1967,
6, 88. (b) Issleib, K.; Walther B. J . Organomet. Chem. 1970, 22, 375-
386.
4920 J . Org. Chem., Vol. 69, No. 15, 2004

Pyrroles from 1-Dialkylamino-3-phosphorylallenes
manually separated from the orange-colored crystals of 2d ,
for which the purification procedure was repeated four times
to furnish a batch of 2d which still contained about 5-10% of
the ammonium salt: IR (KBr) 2203 (s), 1608 (m), 1590 (m),
After cooling, the solvent was evaporated at 15 mbar and the
residue was subjected to flash chromatography [silica gel (100
g), cyclohexane/ethyl acetate ) 3:1]. The crude product mixture
was then dissolved in CH2Cl2 (150 mL), and the solution was
shaken vigorously for a few minutes with 1% aqueous H2O2.
The organic phase was concentrated and submitted to column
chromatography [silica gel (200 g), cyclohexane/ethyl acetate
) 3/1] to furnish pyrrole 6b (0.39 g, 28%) and 10-fluoro-6-
phenyl-3,4,6,12b-tetrahydro-1H-benzo[c][1,4]oxazino[4,3-a]-
azepin-8-yl(diphenyl)phosphanoxide (7b) (0.42 g, 18%). The
latter product was recrystallized from cyclohexane/ethyl ac-
etate (1:2).
Allene 3c was prepared in the same manner from salt 2c
(2.41 g, 4.87 mmol) and was treated analogously to furnish
pyrrole 6c (0.035 g, 2%, after three recrystallizations from
cyclohexane/ethyl acetate ) 3/1).
Allene 3d was prepared analogously from salt 2d (4.76
mmol) which was contaminated with about 10 mol % of
NEt-i-Pr2‚HCl. Thermolysis and workup as described above
furnished pyrrole 6d (0.30 g, 15%) and diphenyl{6-phenyl-2-
[3-(trifluoromethyl)phenyl]-1,2,3,4,6,12b-hexahydrobenzo[c]-
pyrazino[1,2-a]azepin-8-yl}phosphanoxide (7d ) (0.62 g, 21%).
Allene 3e was prepared analogously from salt 2e (2.33 g,
5.10 mmol). The residue left after evaporation of the solvent
was treated with pentane (30 mL) in an ultrasonic bath for 5
min, and after removal of the pentane it was extracted with
toluene (3 × 30 mL). The combined toluene extracts, which
contained 3e (13C NMR δ 206.3 ppm), were left at 20 °C for 24
h, concentrated, and worked up by column chromatography
(see above) to furnish pyrrole 6e which was recrystallized from
cyclohexane/ethyl acetate (3:1): yield 0.46 g (29%).
Data for 3b: 1H NMR (200.13 MHz) δ 2.30-2.45 (m, 4H),
3.50-3.60 (m, 4H), 7.1-7.8 (19H); 13C NMR (50.32 MHz) δ
50.4, 66.7, 111.0 (d, J C,P ) 19.5 Hz), 115.2 (d, J C,F ) 21.6 Hz),
126.8-135.5, 163.0 (d, J C,F ) 251 Hz), 205.1; 31P NMR δ -3.0.
Data for 3c: 1H NMR (CDCl3, 500.14 MHz) δ 2.31-2.42 (m,
4H), 3.55-3.61 (m, 4H), 7.17-7.77 (m, 18H); 13C NMR (CDCl3,
125.77 MHz) δ 50.5, 66.7, 110.3 (d, J C,P ) 20.1 Hz), 126.2-
137.9, 206.5; 31P NMR δ -6.9.
1266 (vs), 1153 (s), 1032 (s), 638 (s) cm-1 1H NMR (500.14
;
MHz) δ 3.51 (pseudo-t, 2H), 3.78 (pseudo-t, 2H), 4.40 (pseudo-
t, 2H), 4.80 (pseudo-t, 2H), 7.07-7.85 (m, 14H); 13C NMR
(125.77 MHz) δ 48.2, 48.7, 53.2, 56.0, 84.0, 112.5, 117.2, 117.9,
119.5 121.9, 122.6, 133.8, 129.0-133.8, 149.0, 162.6. C27H22
F6N2O3S (568.53).
-
Th er m a l Rea ction s of (Dip h en ylp h osp h a n yl)a llen e 3a .
A solution of allene 3a 14 (2.30 g, 5.0 mmol) in anhydrous
toluene (10 mL) was placed in a thick-walled Schlenk tube and
kept at 140 °C for 5 h. After cooling, the mixture was submitted
to flash chromatography [(silica gel (100 g), cyclohexane/ethyl
acetate ) 3/1] to remove high-molecular byproducts as well
as the polar diphenylphosphanoxide which was formed under
these conditions from the reaction product diphenylphosphane.
1
A H NMR spectrum indicated the formation of 5a and 6a in
a 1.4:1 ratio. Separation of the two products was not possible
because of very similar Rf values. The following workup
procedures were chosen: (a) Preparative thick-layer chroma-
tography (silica gel, cyclohexane/ethyl acetate ) 9/1) gave a
small amount of (rel-6R,12bR)-diphenyl-(6-phenyl-3,4,6,12b-
tetrahydro-1H-benzo[c][1,4]oxazino[4,3-a]azepin-8-yl)phos-
phane (5a ) which could not be obtained analytically pure,
however. (b) The solvent was replaced by CH2Cl2 (150 mL),
1% aqueous H2O2 (100 mL) was added, and the mixture was
shaken vigorously. The organic phase was concentrated and
submitted to column chromatography (silica gel (200 g),
cyclohexane/ethyl acetate ) 3/1) to furnish 6,8-diphenyl-3,4-
dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (6a ) (0.165 g, 12%) and
diphenyl(6-phenyl-3,4,6,12b-tetrahydro-1H-benzo[c][1,4]oxazino-
[4,3-a]azepin-8-yl)phosphanoxide (7a ) (0.285 g, 12%). The
latter product was recrystallized from cyclohexane/ethyl ac-
etate (1:2).
Data for 5a : 1H NMR (CDCl3, 500.14 MHz) δ 2.15-2.39 (2
m, 2H), 3.25 (mc, 1H), 3.60 (ddd, J ) 10.9, 10.6, 3.4 Hz), 3.79
(d, J ) 11.0 Hz), 3.97 (mc), 4.13 (dd, J ) 11.8, 3.5 Hz, 1-Hax),
4.41 (d, J ) 11.8 Hz), 5.80 (dd, J ) 6.0, 5.9 Hz), ca. 7.05-7.90
(m, 19H); 31P δ -0.65. Data for 6a : mp 154-155 °C; IR (KBr)
1601 (s), 1490 (m), 1449 (m), 1344 (m), 1096 (s), 753 (s), 694
(s) cm-1; 1H NMR (500.14 MHz) δ 4.03-4.06 (mc, 4H), 5.15 (s,
2H), 6.57 (s), 7.25 (t, J ) 7.0 Hz, 1H), 7.35-7.51 (m, 9H); 13C
NMR (125.77 MHz) δ 44.2, 64.4, 65.1, 107.7, 119.5, 123.5,
125.3, 126.7, 127.0, 128.4, 128.5, 128.6, 132.4, 135.8, 133.7;
MS (EI, 70 eV) m/z (rel int) 275 (M+, 100), 244 (52). Anal. Calcd
for C19H17NO (275.35): C, 82.88; H, 6.22; N, 5.08. Found: C,
82.95; H, 6.22; N, 5.04. Data for 7a : mp 255 °C; IR (KBr) 2840
(w), 2812 (w), 1585 (m), 1435 (m), 1176 (m), 698 (m) cm-1; 1H
Data for 7b: mp 204-5 °C; IR (KBr) 2850 (w), 2812 (w),
1586 (w), 1571 (w), 1487 (m), 1437 (m), 1172 (s), 1121 (s), 699
(s), 527 (s) cm-1 1H NMR (200.13 MHz) δ ) 2.23-2.37 (m,
;
3 3
2H, 4-H), 3.29 (dd, J H,H ) 5.8 Hz, J H,P ) 3.3 Hz, 6-H), 3.53
(dt, 2J H,H ) 3J Hax,Hax ) 10.9 Hz, 3J Hax,Heq ) 4.1 Hz, 3-Hax), 3.62-
3.74 (m, 2H, 3-Heq, 12b-H), 4.08 (dd, 2J H,H ) 12.1 Hz, 3J Hax,Heq
) 3.0 Hz, 1-Hax), 4.35 (d, 2J H,H ) 12.1 Hz, 1-Heq), 6.51 (dd, 3J H,H
) 5.9 Hz, 3J H,P ) 17.8 Hz, 7-H), 6.83, (t, J ) 7.4 Hz, 1H), 7.20-
7.80 (m, 17 Haryl); 13C NMR (50.32 MHz) δ 46.8 (C-4), 56.0
3
(C-12b), 66.9 (C-3), 67.4 (d, J C,P ) 13.4 Hz, C-6), 68.7 (C-1),
114.4 (d, 2J C,F ) 21.5 Hz, C-10), 116.3 (d, 2J C,F ) 22.3 Hz, C-12),
3
2
NMR (500.14 MHz) δ 2.21-2.33 (m, 2H, 4-H), 3.31 (dd, J H,H
127.6-132.4, 137.3, 138.1, 140.3, 140.9, 145.9 (d, J C,P ) 8.8
4
3
) 5.9 Hz, J H,P ) 3.3 Hz, 6-H), 3.56 (dt, 2J , J Hax,Hax )10.8,
1
Hz, C-7), 161.9 (d, J C,F ) 249 Hz, C-11); 31P NMR δ 28.3; MS
10.6 Hz, J Hax,Heq ) 3.5 Hz, 3-Hax), 3.70-3.85 (m, 2H, 3-Heq
,
3
(EI, 70 eV) m/z (rel int) 495 (M+, 35), 294 (M+ - P(O)Ph2, 100).
Anal. Calcd for C31H27FNO2P (495.53): C, 75.14; H, 5.49; N,
2.83. Found: C, 75.11; H, 5.55; N, 2.76. Data for 7d : mp 240
°C; IR (KBr) ν 2816 (m), 1608 (m), 1586 (m), 1495 (s), 1443
12b-H), 4.07 (dd, J H,H ) 12.0 Hz, J Hax,Heq ) 3.5 Hz, 1-Hax),
2
3
4.38 (d, J H,H ) 12.0 Hz, 1-Heq), 6.57 (dd, J H,H ) 5.9 Hz, J H,P
2
3
3
) 18.0 Hz, 7-H), 6.85-8.00 (m, 19 Haryl); 13C NMR (50.32 MHz)
3
(s), 1311 (s), 1197 (vs), 1164 (vs), 1123 (s) cm-1 1H NMR
;
δ 46.8 (C-4), 56.2 (C-12b), 64.9 (C-3), 67.0 (d, J C.P ) 13.4 Hz,
C-6), 68.9 (C-1), 125.1-146.3 (Caryl, 1 Colefin); 31P NMR δ 28.2.
Anal. Calcd for C31H28NO2P (477.54): C, 77.97; H, 5.91; N,
2.93. Found: C, 77.77; H, 6.02; N, 2.90.
(200.13 MHz) δ 2.44-2.54 (m, 2H), 2.89 (pseudo-t, 1H), 3.41-
3.48 (m, 3H), 4.09 (d, J ) 12.3 Hz), 4.14 (s, 1H), 6.64 (dd, J )
18.6, 5.9 Hz, 1H), 7.12-7.90 (m, 23H); 13C NMR (50.32 MHz)
δ 46.0, 48.3, 51.2, 55.8, 66.9 (d), 112.0, 116.1, 118.9, 127.3-
138.0, 141.0, 146.6, 151.1; 31P NMR δ 28.3; MS (EI, 70 eV)
m/z (rel int) 620 (M+, 34), 219 (M+ - P(O)Ph2, 100). Anal. Calcd
for C38H32F3N2OP (620.65): C, 73.54; H, 5.20; N, 4.51. Found:
C, 73.55; H, 5.16; N, 4.43.
Syn th esis of P yr r oles 6a -g fr om Im in iu m Sa lts 2 via
(Dip h en ylp h osp h or yl)a llen es 4. P yr r ole 6a (Meth od A).
A solution of Me3SiOPPh2 (2.03 g, 7.4 mmol) and anhydrous
LiCl (0.42 g, 10.0 mmol) in anhydrous THF (50 mL) was cooled
at -78 °C, and powdered iminium salt 2a 17 (3.16 g, 7.4 mmol)
was added. The mixture was allowed to warm to 20 °C during
12 h. The solvent and Me3SiCl were evaporated at 0.1-0.001
P r epar ation an d Th er m al Reaction s of (Diph en ylph os-
p h a n yl)a llen es 3b-e. Allen e 3b. A solution of iminium salt
2b (2.11 g, 4.76 mmol) and LiCl (0.40 g, 9.44 mmol) in
anhydrous THF (50 mL) was cooled at -78 °C, and Me3SiPPh2
(1.24 g, 4.79 mmol) was added. The solution was allowed to
warm to 20 °C during 12 h, and the solvent as well as formed
Me3SiCl were removed at 0.01 mbar. The solid residue was
extracted three times with toluene (30 mL each time) in an
ultrasonic bath (5 min). The combined toluene extracts were
evaporated to dryness at 0.01 mbar to furnish allene 3b as a
gray-greenish solid which was not purified further. It was
dissolved in dry DMF (30 mL) and heated at 150 °C for 12 h.
J . Org. Chem, Vol. 69, No. 15, 2004 4921

Reisser and Maas
mbar. Anhydrous toluene (30 mL) was added to the black
residue, and the mixture was heated at 100 °C for 5 h. After
cooling, water (150 mL) was added and the mixture was
extracted with 3 × 50 mL of ether. The combined organic
phases were washed with water (50 mL) and dried (CaCl2),
and the solvent was removed at 15 mbar. The dark-brown
residue was separated by column chromatography (silica gel
(200 g), cyclohexane/ethyl acetate ) 3/1) to furnish subse-
quently pyrrole 6a and a fraction that contained a trace of 7a
together with other phosphorus-containing products. The yield
of 6a after recrystallization from ether was 0.49 g (24%); see
above for physical data.
(r el-6R,12bR)-8-(4-Flu or oph en yl)-6-ph en yl-3,4-dih ydr o-
1H-p yr r olo[2,1-c][1,4]oxa zin e (6b). Prepared from iminium
salt 2b (4.43 g, 10 mmol) by Method A: yield 1.95 g (66%),
after recrystallization from cyclohexane/ethyl acetate (3:1); mp
145-146 °C; IR (KBr) 1525 (s), 1497 (s), 1222 (s), 1157 (s),
1089 (s), 987 (m), 842 (s), 756 (m) cm-1; 1H NMR (500.14 MHz)
δ 4.01-4.06 (m, 4H), 5.08 (s, 2H), 6.49 (s, 1H), 7.08-7.50
(several m, 9H); 13C NMR (125.77 MHz) δ 44.1, 64.2, 64.8,
107.6, 115.3 (d, J C,F ) 21.3 Hz), 128.0 (d, J C,F ) 7.7 Hz), 131.9
(d, J C,F ) 3.1 Hz), 160.1 (d, J C,F ) 244.3 Hz), 118.5, 123.2, 126.9,
128.3, 128.5, 132.3, 133.7; MS (EI, 70 eV) m/z (rel int) 294 (19),
293 (M+, 100), 292 (48), 262 (64). Anal. Calcd for C19H16FNO
(293.34): C, 77.80; H, 5.50; N, 4.77. Found: C, 77.42; H, 5.29;
N, 4.71.
g, 6.14 mmol), and LiCl (0.42 g, 10.0 mmol) in THF (50 mL)
as described in method A. This reaction mixture was allowed
to come from -78 to +20 °C within 12 h and then left at room
temperature for an additional 24 h. The solvent was evapo-
rated, and the residue was dissolved in ether, washed with
water, and dried (CaCl2). Column chromatography [silica gel
(200 g), cyclohexane/ethyl acetate ) 3:1] provided 6e which
was recrystallized from ether: yield 0.80 g (43%); mp 162 °C;
IR (KBr) 1601 (vs), 1468 (s), 1453 (s), 1443 (s), 1174 (s), 753
1
(vs), 726 (vs), 702 (s) cm-1; H NMR (500.14 MHz) δ 5.13 (s,
2H), 6.76 (s, 1H), 7.17-7.79 (m, 14H); 13C NMR (125.77 MHz)
δ 51.1, 111.5, 118.8, 119.1, 122.8, 124.9, 125.2, 126.0, 126.4,
127.8, 127.9, 128.6, 128.8, 131.1, 132.6, 133.2, 135.6, 136.3,
140.0. Anal. Calcd for C23H17N (307.39): C, 89.87; H, 5.57; N,
4.55. Found: C, 89.70; H, 5.68; N, 4.38.
8-(1,3-Ben zod ioxol-5-yl)-6-p h en yl-3,4-d ih yd r o-1H-p yr -
r olo[2,1-c][1,4]oxa zin e (6f) a n d (r el-6R,12bR)-Dip h en yl-
(6-p h en yl-3,4,6,13b-tetr a h yd r o-1H-[1,3]d ioxolo[4’,5’:4,5]-
ben zo[c][1,4]oxazin o[4,3-a ]azepin -8-yl)ph osph an oxide (7f)
(Meth od B). A solution of salt 2f (5.10 mmol) in CH2Cl2 (40
mL), obtained by the general procedure, was cooled at -78
°C. Me3SiOPPh2 (1.40 g, 5.10 mmol) and LiCl (0.84 g, 10.0
mmol) were added, and the mixture was allowed to come to
20 °C during 12 h. Thermolysis in toluene and workup was
done as described in method A. Column chromatography [silica
gel (200 g), elution with cyclohexane/ethyl acetate mixture,
first 3/1 (∼1 L), then 1/1] furnished successively pyrrole 6f,
dihydrobenzazepine 7f, and several unidentified phosphorus-
containing byproducts. Yield of 6f after recrystallization from
ether: 0.19 g (11%); yield of 7f after recrystallization from
cyclohexane/ethyl acetate (1:1): 1.00 g (38%). Data for 6f:
colorless tiny needle crystals; mp 151 °C; IR (KBr) 1598 (m),
1497 (s), 1485 (s), 1336 (m), 1228 (vs), 1093 (s), 1039 (s), 764
(r el-6R,12b R)-8-(3,4-Dich lor op h en yl)-6-p h en yl-3,4-d i-
h yd r o-1H-p yr r olo[2,1-c][1,4]oxa zin e (6c). Prepared from
iminium salt 2c (2.47 g, 5.0 mmol) by Method A: yield 1.33 g
(77%), after recrystallization from ether; pale yellow crystals;
mp 130-131 °C; IR (KBr) 1591 (m), 1482 (s), 1136 (s), 1099
(s), 988 (m), 758 (s), 700 (s) cm-1 1H NMR (500.14 MHz) δ
;
3.97 (s, 4H), 5.00 (s, 2H), 6.40 (s, 1H), 7.05 (dd, J ) 8.0, 2.0
Hz, 1H), 7.27-7.39 (m, 7H); 13C NMR (125.77 MHz) 44.1, 64.2,
64.7, 107.4, 117.1, 124.1, 125.7, 127.2, 128.1, 128.4, 128.5,
1
(s) cm-1; H NMR (500.14 MHz) δ 4.01 (s, 4H), 5.03 (s, 2H),
5.94 (s, 2H), 6.40 (s, 1H), 6.74 (d, J ) 8.0 Hz, 1H), 6.82 (d, J
) 8.0 Hz, 1H), 6.83 (s, 1H), 7.25-7.45 (m, 5H); 13C NMR
(125.77 MHz) δ 44.2, 64.3, 64.9, 100.8, 107.5, 107.7, 108.4,
119.3, 119.9, 123.0, 126.9, 128.4, 128.5, 129.9, 132.4, 133.5,
145.4, 147.8. Anal. Calcd for C20H17NO3 (319.36): C, 75.22;
H, 5.36; N, 4.38. Found: C, 74.94; H, 5.38; N, 4.29. Data for
7f: yellowish crystalline solid; mp 221-222 °C; IR (KBr) 2887
(w), 2849 (w), 2810 (w), 1497 (m), 1481 (vs), 1247 (s), 1176 (s),
128.7, 130.4, 132.0, 132.5, 134.0, 136.0. Anal. Calcd for C19H15
-
Cl2NO (344.24): C, 66.29; H, 4.39; N, 4.07. Found: C, 66.40;
H, 4.42; N, 4.02.
6,8-Dip h en yl-2-[3-(tr iflu or om eth yl)p h en yl]-1,2,3,4-tet-
r a h yd r op yr r olo[1,2-a ]p yr a zin e (6d ). Prepared from imi-
nium salt 2d (3.38 g, 5.94 mmol, contaminated with additional
0.09 g of NEtiPr2‚HCl), Me3SiOPPh2 (1.63 g, 5.94 mmol), and
LiCl (0.42 g, 10.0 mmol) according to method A. Because of
the high oxidation semsitivity of the pyrrole, column chroma-
tography was carried out under nitrogen atmosphere with
silica gel that had been kept at 0.001 mbar for several days
and had been purged with argon. Thus, the following products
were obtained in the given order: pyrrole 6d (1.43 g, 57%),
1,3-diphenyl-1-{4-[3-(trifluoromethyl)phenyl]piperazino}-2-pro-
pynyl(diphenyl)phosphanoxide (10) (0.30 g, 8%), and dihy-
drobenzazepine 7d (0.06 g, 1.6%). Data for 6d : obtained as a
yellow glassy solid which did not crystallize; air-sensitive; IR
(KBr) 1606 (m), 1494 (m), 1449 (m), 1315 (m), 1120 (s), 759
(m), 696 (s) cm-1; 1H NMR (200.13 MHz) δ 3.31 (pseudo-t, 2H),
3.97 (pseudo-t, 2H), 4.58 (s, 2H), 6.42 (s, 1H), 6.82-7.48 (m,
14H); 13C NMR (50.32 MHz) δ 43.9, 45.9, 46.1, 108.0, 110.8,
115.3, 117.6, 120.2, 123.3, 125.4, 126.8, 126.9, 128.0, 128.5,
128.6, 129.7, 131.3, 132.2, 133.3, 135.8, 149.6. Anal. Calcd for
1122 (s), 1041 (s), 700 (vs), 565 (vs) cm-1 1H NMR (200.13
;
MHz) δ 2.20-2.42 (m, 2 H) 3.28 (dd, J H,H ) 5.9, 3.4 Hz, 1H),
3.57 (dt, J ) 10.9, 3.1 Hz, 1H), 3.72-3.78 (m, 2H), 4.07 (dd, J
) 11.9, 3.5 Hz, 1H), 4.32 (d, J ) 11.9 Hz, 1H), 5.93/5.96 (AB
system, 2J ) 5.9 Hz, 2H), 6.46 (dd, J ) 18.2, 5.9 Hz, 1H), 7.03
(s, 1H), 7.20-7.80 (m, 16H); 13C NMR (50.32 MHz) δ 46.8, 56.1,
66.9, 67.7 (d, J C,P ) 13.3 Hz), 69.1, 101.2, 108.3, 109.6, 127.6-
147.5; 31P NMR δ 28.3; MS (EI, 70 eV) m/z (rel int) 521 (M+,
3.8), 320 (M+ - P(O)Ph2, 25). Anal. Calcd for C32H28NO4P
(521.55): C, 73.69; H, 5.41; N, 2.69. Found: C, 73.77; H, 5.39;
N, 2.64.
Syn t h esis of P yr r oles
6 fr om E n a m in ok et on es 9
(Meth od C). 6-(2-Br om op h en yl)-8-(4-ch lor op h en yl)-3,4-
d ih yd r o-1H-p yr r olo[2,1-c][1,4]oxa zin e (6h ). A solution of
triflic anhydride (34.68 g, 0.12 mol) in CH2Cl2 (350 mL) was
cooled at -78 °C in an acetone/dry ice bath, and neat
enaminoketone 9h (50.00 g, 0.12 mol) was added. The cooling
bath was removed, and the solution was allowed to assume
20 °C within 30 min, left at this temperature for 15 min, and
cooled again to -78 °C. Diisopropylethylamine (15.88 g, 21.0
mL, 0.12 mol) was added, and the solution was allowed to come
to 20 °C within 30 min, thereby developing a dark-red color.
The solution of the so formed propyne iminium salt 2h was
cooled again at -78 °C, and Me3SiOPPh2 (33.72 g, 0.12 mol)
and anhydrous LiCl (5.50 g, 0. 13 mol) were added. The
mixture was then brought to room temperature within 12 h,
and most of the solvent together with formed Me3SiCl was
distilled off. The remaining volatiles were evaporated at 0.01
mbar. The residue was dissolved in anhydrous toluene (250
mL) and heated at 100 °C for 5 h. After cooling, the mixture
C
26H21F3N2 (418.46): C, 74.63, H, 5.06, N, 6.69. Found: C,
74.22, H, 4.80, N, 6.55. Data for 10: mp 172 °C (recryst from
cyclohexane/ethyl acetate (1:2)); IR (KBr) 1612 (m), 1448 (m),
1189 (s), 1116 (s), 693 (s) cm-1; 1H NMR (200.13 MHz) δ 2.72-
2.85 (m, 2H, NCH2), 3.08-3.30 (m, 6 H), 7.00-7.72 (m, 22H),
8.05-8.15 (m, 2H); 13C NMR (50.32 MHz) δ 48.7 (2 C), 49.2
(d, J C,P ) 5.0 Hz), 71.4 (d, J C,P ) 81.7 Hz), 84.0, 94.3 (d, J C,P
)
8.3 Hz), 111.7, 115.5, 118.4, 121.5, 122.0, 126.9-135.2, 151.1;
31P NMR δ 30.2; MS (EI, 70 eV) m/z (rel int) 621 (M+, 2.6),
620 (M+, 7.4), 419 (M+ - P(O)Ph2, 100). Anal. Calcd for
C
38H32N2F3OP (620.65): C, 73.54; H, 5.20; N, 4.51. Found: C,
73.55; H, 5.02; N, 4.42.
1,3-Dip h en yl-5H-p yr r olo[2,1-a ]isoin d ole (6e). Prepared
from iminium salt 3e (2.81 g, 6.14 mmol), Me3SiOPPh2 (1.68
4922 J . Org. Chem., Vol. 69, No. 15, 2004

Pyrroles from 1-Dialkylamino-3-phosphorylallenes
was poured into water (500 mL). The toluene was collected,
and the aqueous phase was extracted with CH2Cl2 (3 × 100
mL). The combined organic phases were washed with water
(150 mL), dried (CaCl2), and concentrated. The residue was
separated by column chromatography [silica gel (1000 g),
cyclohexane/ethyl acetate ) 5:1]. After recrystallization from
cyclohexane/ethyl acetate (1:1), pyrrole 6h was obtained as
yellow crystals: yield 22.43 g (47%); mp 115 °C; IR (KBr) 1594
79.97; H, 6.71; N, 4.05. Found: C, 79.91; H, 6.74; N, 4.08. Data
for 6jB: mp 114 °C; IR (KBr) 1727 (vs), 1600 (s), 1309 (s), 1190
(vs), 1171 (vs), 766 (vs), 701 (vs) cm-1; 1H NMR (500.14 MHz)
δ 1.18 (t, J ) 7.1 Hz), 1.84-1.92 (mc, 1H), 2.15-2.22 (mc, 1H),
2.74-2.80 (mc, 1H), 2.90-2.97 (mc, 1H), 3.07-3.13 (m, 1H),
4.03-4.14 (m, 4H), 6.43 (s, 1H), 7.12-7.43 (m, 10H); 13C NMR
(125.77 MHz) δ 13.9, 22.6, 24.0, 39.9, 45.6, 60.7, 108.3, 120.1,
124.8, 125.7, 126.6, 126.9, 128.2, 128.3, 128.5, 132.8, 133.1,
136.4, 172.5; MS (EI, 70 eV) m/z 345 (M+, 100). Anal. Calcd
for C23H23NO2 (345.44): C, 79.97; H, 6.71; N, 4.05. Found: C,
79.92; H, 6.59; N, 3.98.
(m), 1555 (m), 1484 (s), 1104 (s), 1091 (s), 834 (s), 750 (s) cm-1
;
1H NMR (500.14 MHz) δ 3.76 (pseudo-t, 2H), 4.00 (pseudo-t,
2H), 5.02 (s, 2H), 6.37 (s, 1H), 7.20-7.45 (m, 7H), 7.63 (d, J )
7.9 Hz, 1H); 13C NMR (125.77 MHz) δ 43.3, 64.2, 64.8, 108.1,
117.7, 123.0, 125.3, 127.2, 127.7, 128.6, 129.8, 130.7, 131.8,
132.8, 132.9, 133.5, 134.3. Anal. Calcd for C19H15BrClNO
(388.69): C, 58.86; H, 3.90; N, 3.61. Found: C, 58.74, H, 3.95;
N, 3.51.
1-Meth yl-2,3,5-tr ip h en ylp yr r ole (6k ). Prepared according
to method C from enaminoketone 9k (1.70 g, 5.20 mmol). The
product obtained after column chromatography [silica gel (200
g), cyclohexane/ethyl acetate ) 3:1] was recrystallized from
ether: yield 0.39 g (24%); mp 178 °C. Melting point and NMR
data agree with reported data.29 Anal. Calcd for C23H19
N
P yr r ole 6e. Prepared according to method C from enami-
noketone 9e (1.63 g, 5.00 mmol). After the reaction with Me3-
SiOPPh2/LiCl, the CH2Cl2 solution was kept at 20 °C for 1 day.
The solvent was evaporated and the residue was separated
by column chromatography [silica gel (200 g), cyclohexane/
ethyl acetate ) 3/1] to furnish pyrrole 6e which was recrystal-
lized from ether: yield 0.60 g, 39%. See above for physical and
spectroscopic data.
1-(1,3-Ben zod ioxol-5-yl)-3-p h en yl-5,6-d ih yd r op yr r olo-
[2,1-a ]isoqu in olin e (6g). Prepared according to method C
from enaminoketone 9g (3.62 g, 9.40 mmol). After the reaction
with Me3SiOPPh2/LiCl, the CH2Cl2 solution was kept at 20
°C for 1 day. Workup as described above for 6e furnished
pyrrole 6g as the only product: yield 1.54 g (45%); yellow solid;
mp 155-156 °C; IR (KBr) 1600 (m), 1491 (s), 1479 (s), 1237
(s), 1229 (s), 1042 (s), 938 (m), 701 (m) cm-1; 1H NMR (200.13
MHz) δ 2.88 (t, J ) 6.1 Hz, 2H), 3.98 (t, J ) 6.1 Hz, 2H), 5.83
(s, 2H), 6.28 (s, 1H), 6.70-7.40 (m, 12H); 13C NMR (50.32 MHz)
δ 30.1, 42.2, 100.7, 108.3, 109.5, 111.0, 122.1, 122.4, 124.3,
125.4, 125.5 (2C), 126.8, 127.5, 128.3, 128.5, 129.8, 131.2,
132.2, 132.3, 133.2, 146.0, 147.5; MS (EI, 70 eV) m/z 365 (M+,
100). Anal. Calcd for C25H19NO2 (365.43): C, 82.17; H, 5.24;
N, 3.83. Found: C, 82.10; H, 5.33; N, 3.80.
(309.41): C, 89.28; H, 6.19; N, 4.53. Found: C, 89.18; H, 6.20;
N, 4.55.
N-[2-(2-Oxo-3,5-diph en yl-2,5-dih ydr o-1H-pyr r olyl)eth yl]-
N-[3-(tr iflu or om eth yl)p h en yl]for m a m id e (13) a n d N-[2-
(2-Hyd r oxy-5-oxo-2,4-d ip h en yl-2,5-d ih yd r o-1H-p yr r olyl)-
et h yl]-N-[3-(t r iflu or om et h yl)p h en yl]for m a m id e (14). A
mixture of compounds was formed when pyrrole 6d (1.00 g)
was stored for 2 weeks under air. This mixture was subjected
to column chromatography [silica gel (250 g), cyclohexane/ethyl
acetate ) 5:1] which furnished first 14 and then 13. Similar
Rf values and continuing oxidative decomposition prevented
the complete purification of the two products. However, after
repeated column chromatography, a sample (∼0.13 g) of
sufficiently pure 14 was obtained and was fully characterized,
while the air-sensitive compound 13 could only be character-
ized by NMR spectrroscopy. Data for 14: IR (KBr) 3236 (br,
m), 1686 (vs), 1649 (s), 1342 (s), 1326 (s), 1169 (s), 1121 (s),
693 (s) cm-1; 1H NMR (500.14 MHz) δ 2.86 (broadened d, 2J )
2
14.8 Hz, 1H), 3.32 (broadened d, J ) 14.3 Hz, 1H), 3.98 (mc,
1H), 4.76 (mc 1H), 6.03 (s, 1H, OH), 7.06 (s, 1 H), 7.32-7.88
(m, 14H), 8.18 (s, 1H); 13C NMR (125.77 MHz) δ 37.3, 46.3,
90.4, 122.3, 124.5, 125.9, 126.7, 127.4, 128.4, 128.7, 128.9,
129.4, 130.4, 130.7, 132.1 (q, J C,F ) 32.9 Hz), 133.2, 137.2,
141.1, 144.5, 163.8, 169.7; MS (EI, 70 eV) m/z (rel int) 466 (M+,
80), 438 (M+ - CO, 8), 277 (20), 235 (100). Anal. Calcd for
1,3-Dip h e n yl-6,7,8,9-t e t r a h yd r o-5H -p yr r olo[1,2-a ]-
a zep in e (6i). Prepared according to method C from enami-
noketone 9i (2.98 g, 9.78 mmol). The product obtained after
column chromatography was recrystallized three times from
cyclohexane/ethyl acetate (1:1) to furnish 0.45 g (16%) of 6i as
a waxlike solid: mp 130-131 °C, in agreement with the
literature;30 IR (KBr) 1602 (s), 1487 (m), 1393 (m), 1345 (m),
C
26H21F3N2O3 (466.46): C, 66.95, H, 5.62, N, 6.00. Found: C,
66.88, H, 5.46, N, 5.57. Data for 13: 1H NMR (500.14 MHz) δ
2.98 (mc, 1H), 3.73 (m, J ) 14.0 Hz, 1H), 4.00 (m, 1H), 4.14
(m, 1H), 5.34 (d, 3J ) 1.9 Hz), 7.10-7.55 (m, 15H), 8.28 (s,
1H); 13C NMR (125.77 MHz) δ 38.0, 43.1, 63.8, 120.5-134.6,
140.93, 140.95, 162.0, 170.3; MS (EI, 70 eV) m/z 450 (M+, 100);
1
756 (s), 707 (s), 698 (s) cm-1; H NMR (200.13 MHz) δ 1.68-
1.92 (m, 6H), 2.90-2.95 (m, 2H), 3.98-4.02 (m, 2H), 6.23 (s,
1H), 7.15-7.42 (m, 10H); 13C NMR (50.32 MHz) δ 25.8, 27.8,
29.5, 31.1, 46.4, 108.0, 121.5, 125.2, 126.6, 128.3, 128.4, 128.6,
129.1, 133.3, 133.4, 133.6, 137.5; MS (EI, 70 eV) m/z 287 (M+,
100). Anal. Calcd for C21H21N (287.40): C, 87.76; H, 7.36; N,
4.87. Found: C, 87.50; H, 7.30; N, 4.72.
C
26H21F3N2O2 (450.46).
Dip h en yl[3,5-d ip h en yl-1-{2-[3-(tr iflu or om eth yl)a n ili-
n o]eth yl}-1H-p yr r ol-2-yl]m eth ylp h osp h a n oxid e (15). The
synthesis was carried out in complete analogy to that of 6d
according to method A, but with 2 equiv of Me3SiOPPh2,
starting from 2.84 g (5.00 mmol) of salt 2d (contaminated with
additional 0.08 g of NEtiPr2‚HCl), 2.74 g (10.0 mmol) of Me3-
SiOPPh2, 0.42 g (10.0 mmol) of LiCl. Column chromatography
[silica gel (250 g), cyclohexane/ethyl acetate ) 1:1] provided,
after recrystallization from the same solvent mixture, 1.02 g
(33%) of 15 as a colorless powder: mp 169-170 °C; IR (KBr)
Eth yl 1,3-Dip h en yl-5,6,7,8-tetr a h yd r oin d olizin e-8-ca r -
boxyla te (6jA) a n d Eth yl 1,3-Dip h en yl-5,6,7,8-tetr a h y-
d r oin d olizin e-6-ca r boxyla te (6jB). Prepared according to
method C from enaminoketone 9j (1.90 g, 5.2 mmol). Column
chromatography [silica gel (200 g), cyclohexane/ethyl acetate
) 3/1] gave a mixture of pyrroles 6jA and 6jB (0.66 g, 39%)
which could be separated chromatographically using cyclo-
hexane/ethyl acetate (11:1) as the eluent: (a) 6jA (0.19 g, 11%);
(b) 6jB (0.45 g, 25%). Data for 6jA: yellow oil; 1H NMR (500.14
MHz) δ 1.17 (t, J ) 7.1 Hz), 1.91 (mc, 1H), 2.21 (mc, 3H), 3.97-
3.99 (m, 1H), 4.08 (q, J ) 7.1 Hz), 4.14-4.18 (m, 1H), 4.34-
4.37 (m, 1H), 6.56 (s, 1H), 7.30-7.58 (m, 10H); 13C NMR
(CDCl3, 125.77 MHz) δ 13.6, 20.9, 25.0, 40.1, 44.4, 60.4, 108.7,
122.2, 123.0, 125.1, 126.4, 127.4, 127.9, 128.0, 128.4, 132.8,
133.2, 136.4, 173.3. Anal. Calcd for C23H23NO2 (345.44): C,
3302 (s), 1614 (s), 1438 (s), 1341 (vs), 1315 (s), 1117 (vs), 741
3
(vs), 695 (vs) cm-1; 1H NMR (500.14 MHz) δ ) 3.16 (t, J H,H
)
6.0 Hz, 2H), 3.88 (d, J P,H ) 12.8 Hz,), 4.49 (t, J H,H ) 6.0 Hz,
2H), 6.14 (s, 1H), 6.35 (d, J ) 8.1 Hz), 6.50 (s, 1H), 6.81-7.45
(m, 22H); 13C NMR (125.77 MHz) δ 28.5 (d, J C,P ) 67.4 Hz),
43.7, 44.4, 108.7, 110.7, 113.4, 115.2, 120.1 (d, J C,P ) 10.2 Hz),
125.6 (d), 129.5, 135.3, 147.8, 125.7-136.6; 31P NMR δ 30.5;
MS (EI, 70 eV) m/z 620 (M+, 22). Anal. Calcd for C38H32F3N2-
OP (620.65): C, 73.54; H, 5.20; N, 4.51. Found: C, 73.44; H,
5.29; N, 4.40.
7-Br om o-6-(2-br om op h en yl)-8-(4-ch lor op h en yl)-3,4-d i-
h yd r o-1H-p yr r olo[2,1-c][1,4]oxa zin e (16). A suspension of
N-bromosuccinimide (0.89 g, 5.00 mmol) and AlBr3 (0.13 g, 0.50
(30) (a) Gotthardt, H.; Huisgen, R. Chem. Ber. 1970, 103, 2625-
2632. (b) Armesto, D.; Horspool, W. M.; Ortiz, M. J .; Romano, S. J .
Chem. Soc., Perkin Trans. 1 1992, 171-175.
J . Org. Chem, Vol. 69, No. 15, 2004 4923

Reisser and Maas
mmol) in CH2Cl2 (40 mL) was cooled at -78 °C, pyrrole 6h
(1.94 g, 4.99 mmol) was added, and the mixture was allowed
to come to 20 °C within 12 h. The precipitated succinimide
was removed by filtration, and the filtered solution was
extracted with water (3 × 50 mL). The organic phase was
dried, the solvent was evaporated (15 mbar), and the residue
was purified by column chromatography [silica gel (200 g),
cyclohexane/ethyl acetate ) 5:1]. The product was dissolved
in the minimum amount of the same solvent mixture from
which it crystallized after ∼3 weeks as a colorless powder:
yield 1.33 g (57%); mp 143-144 °C; IR (KBr) 1484 (s), 1328
(s), 1185 (s), 1105 (vs), 1090 (vs), 835 (s), 754 (s) cm-1; 1H NMR
(200.13 MHz) δ 3.52-3.64 and 3.74-3.85 (2 m, AA′ of AA′BB′),
by filtration, washed with ether (3 × 50 mL), and then added
to 5% aq HCl (100 mL). The precipitated product was then
isolated by filtration and recrystallized from ethyl acetate to
furnish yellow crystals (1.11 g, 63%): mp 208 °C; IR (KBr)
3150-2646 (br, m), 1701 (vs), 1486 (s), 1301 (s), 1275 (s), 1084
(vs), 827 (m), 795 (m), 764 (m) cm-1 1H NMR (pyridine-d5,
;
200.13 MHz) δ 3.88 (s, 4H), 5.05 (s, 2H), 6.65 (s, 1H), 7.20-
7.60 (m, 7H), 8.34 (d, J ) 6.6 Hz, 1H); 13C NMR (pyridine-d5,
125.77 MHz) δ 43.6, 64.3, 65.1, 107.7, 117.7, 127.9, 128.1,
128.3, 128.4, 129.0, 130.3, 130.5, 131.3, 132.9, 133.0, 133.1,
134.7, 170.3; MS (EI, 70 eV) m/z 355 (M+, 33), 354 (M+, 32),
353 (M+, 100). Anal. Calcd for C20H16ClNO3 (353.80): C, 67.89;
H, 4.56; N, 3.96. Found: C, 67.80, H, 4.74, N, 3.93.
2
3.92-3.12 (m, 2H), 4.80/4.89 (AB system, J ) 14.4 Hz, 2H),
7.22-7.45 (m, 7H), 7.68 (d, J ) 7.9 Hz, 1H); 13C NMR (50.32
MHz) δ 43.4, 64.0, 64.4, 97.1, 117.2, 123.6, 126.0, 127.5, 128.4,
130.0, 130.5, 130.6, 131.9, 132.0, 132.2, 132.9, 133.7. Anal.
Calcd for C19H14Br2ClNO (467.59): C, 48.81; H, 3.18; N, 2.99.
Found: C, 48.98; H, 3.09; N, 2.87.
Ack n ow led gm en t. Financial support of this work
by the Fonds der Chemischen Industrie is gratefully
acknowledged. We also thank Birgit Horn for her
assistance in the synthetic work.
2-[8-(4-Ch lor oph en yl)-3,4-dih ydr o-1H-pyr r olo[2,1-c][1,4]-
oxa zin -6-yl]ben zoic Acid (17). Magnesium turnings (0.12
g, 5.0 mmol) were placed in anhydrous THF (5 mL) and
activated successively with 1,2-dibromoethane, Me3SiCl, and
treatment in an ultrasonic bath (15 min). Pyrrole 6h (1.94 g,
5.0 mmol) was added, and the mixture was heated at 100 °C
for 12 h. After the metal had been consumed completely, the
solution was poured into THF (150 mL) and CO2 gas was
bubbled through the liquid. The precipitated salt was isolated
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and physical/spectroscopic data for compounds 2b-e, 5a ,
6a -k , 7a ,b,d ,f, and 13-17; peak assignment of 1H and 13C
NMR spectral data for compounds 5a , 6a -k , and 7a ,b ,d ,f;
NMR spectra of compounds 2d , 3b,c, 5a , 13, and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O049586O
4924 J . Org. Chem., Vol. 69, No. 15, 2004