Progress in carbonylative [2+2+1] cycloaddition: Utilization of a nitrile group as the πa component

Article abstract of DOI:10.1002/anie.201305729

New tricks, old reactions: The treatment of 2-(1,2-propadienyl) phenylacetonitrile derivatives with a catalytic amount of [{RhCl(CO)dppp} ₂] (dppp=1,3-bis(diphenylphosphanyl)propane) under a CO atmosphere produced benzo[f]oxyindole derivatives

Full text of DOI:10.1002/anie.201305729

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DOI: 10.1002/anie.201305729
Heterocycles
Progress in Carbonylative [2+2+1] Cycloaddition: Utilization of
a Nitrile Group as the p Component**
Takashi Iwata, Fuyuhiko Inagaki, and Chisato Mukai*
The Pauson–Khand reaction (PKR)[1] of the enynes A
provides the most straightforward as well as powerful
methodology for the construction of the cyclopentenone-
fused cyclic frameworks B (Scheme 1). Several so-called
Pauson–Khand-type [2+2+1] reactions (PKTR) using an
During our continuous investigations of the carbonylative
[2+2+1] cycloaddition,[6b,d,8] we noticed that the two allenyl
functionalities [e.g., E (X = CH2) in Scheme 2] served as the
proper combination of two p components ending up with the
efficient construction of the carbonylative [2+2+1] prod-
Scheme 1. [2+2+1] Cycloaddition of two p components and carbon
monoxide.
Scheme 2. Rhodium(I)-catalyzed HPKTR of 1a. dppp=1,3-bis(diphe-
nylphosphanyl)propane.
alternative p component[2] instead of the alkyne or alkene
p bond of A have also been developed. In contrast, these
reactions would generally be referred to as the hetero-
Pauson–Khand-type reaction (HPKTR) if more than one
carbon atom of the newly generated cyclopentenone frame-
work of B was replaced by an oxygen atom or nitrogen
functionalities. Both ketone[3] and aldehyde[3f,4] groups (oxa-
alkene p bond) have been employed in this context, and the
imine functionalities[3f,4c,5] were shown to serve as the aza-
alkene p bond. Furthermore, the carbodiimide groups (diaza-
allene)[6] provided an alternative aza-alkene p bond. The
nitrile group can be used as an aza-alkyne p bond in the
transition-metal-catalyzed [2+2+2] cyclcoaddition,[7] but this
has not been the case in which the nitrile group served as
a p component in the carbonylative [2+2+1] cycloaddition.
This study describes the unprecedented intramolecular rho-
dium(I)-catalyzed carbonylative [2+2+1] cycloaddition of the
nitrile-allene substrates C and CO leading to the construction
of the azabicyclo[m.3.0] frameworks D.
ucts.[8] We envisaged that if the phenylketenimine species such
as E (X = NH; isoelectronic structure of allene) could be
generated in situ from the phenylacetonitrile group, the
resulting phenylketenimine intermediate might subsequently
react with the allene counterpart under a CO atmosphere as
in the case of bis(allene)s. In contrast, the phenylsulfonyl-
substituted allenes have been utilized as substrates for most of
our allenyne, allenene, and bis(allene) cyclometallation
reactions[8,9] because of their ready availability as well as
their ability to selectively react at the terminal double bond.
Thus, our initial evaluation for the rhodium(I)-catalyzed
carbonylative [2+2+1] cycloaddition of nitrile-allene sub-
strates was performed using the o-allenylphenylacetonitrile
1a having a phenylsulfonyl group on the allenyl moiety
(Scheme 2). A solution of 1a with 10 mol% [{RhCl(CO)2}2] in
toluene was refluxed under a CO atmosphere, but produced
an intractable mixture. Changing the rhodium(I) catalyst to
[{RhCl(CO)dppp}2] (1 h reflux in toluene) gratifyingly pro-
duced the desired benzo[f]oxyindole derivative 2a in 60%
yield,[10] which should have been derived by the formal
[2+2+1] cycloaddition of the distal double bond of the allene,
ketenimine (or nitrile intact), and CO.[11] Increasing the
loading amounts of the rhodium(I) catalyst (20 mol%
[{RhCl(CO)dppp}2]) produced a better yield (74%) of 2a.[12]
Our endeavor then focused on the application of suitable
reaction conditions (10 mol% [{RhCl(CO)dppp}2] in reflux-
ing toluene under an atmosphere of CO)[13] to other nitrile-
allene substrates. The results are summarized in Table 1,
including our initial result with 1a (entry 1). The nitrile-
phenylsulfonylallene substrate 1b having a methoxy group at
the p-position of the cyanomethyl group afforded the
[*] T. Iwata, Dr. F. Inagaki, Prof. Dr. C. Mukai
Division of Pharmaceutical Sciences
Graduate School of Medical Sciences
Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: mukai@p.kanazawa-u.ac.jp
[**] This work was supported in part by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology (Japan), for which we are thankful.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305729.
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Table 1: [{RhCl(CO)dppp}2]-catalyzed HPKTR of 1.
Scheme 3. Dephenylsulfonylation of 2a. AIBN=2’,2’-azobis(2-methyl-
propionitrile).
Entry
Substrate
R1
R2
R3
t [h]
Yield [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
Me
Me
Me
Me
Me
H
OMe
Cl
H
H
H
OMe
1
4
3
5
3
1.5
5
31
0.5
2
4
0.5
0.5
2a: 60
2b: 79
2c: 54
2d: 26
2e: 37
2 f: 88
2g: 65
2h: 62
2i: 72
2j: 66
2k: 79
2l: 80
2m: 15
H
OCH2O
H
OMe
Cl
NO2
H
H
H
H
H
9
Scheme 4. Rhodium(I)-catalyzed HPKTR of methylallenes 3.
10
11
12
13
1j
1k
1l
OMe
Me
Me
H
OCH2O
H
H
NO2
H
1m
the substituent at the a position to the nitrile group was
tolerated in this ring-closing reaction (Scheme 4). In fact, the
methylallene-nitrile derivative 3 produced the dimethyl
compound 4 in 68% yield. Thus, it is concluded that nitrile-
methylallene derivatives consistently produced the benzo-
[f]oxyindole derivatives in good yields irrespective of the
electronic property of the substituent on the benzene ring.
The two plausible mechanisms for the production of the
benzo[f]oxyindole skeletons 2 and 4 could be tentatively
interpreted by either of the following two routes (Scheme 5).
corresponding [2+2+1] cycloadduct 2b in a higher yield
(entry 2). Similarly, the chloro derivative 1c furnished 2c in
54% yield (entry 3). Upon exposure of compound 1d, having
a methoxy group at the p-position of the allene functionality,
to the standard reaction conditions for 5 hours, however, the
yield of the product 1d drastically decreased to 26%
(entry 4). A similar low yield (37%) was observed when the
methylenedioxy derivative 1e was treated with the rho-
dium(I) catalyst (entry 5). It was found that the introduction
of a methyl group instead of a phenylsulfonyl group to the
allenyl moiety consistently produced the benzo[f]oxyindole
framework in good yields. Indeed, the exposure of 1 f to the
rhodium(I) catalyst produced the benzo[f]oxyindole deriva-
tive 2 f in 88% yield (entry 6). Similar treatment of both the
methoxy (1g) and chloro (1h) derivatives afforded the
corresponding ring-closed products 2g and 2h in the respec-
tive yields of 65 and 62% (entries 7 and 8). Introduction of
a nitro group at the p-position of the cyanomethyl group did
not affect the reaction and 1i smoothly provided the desired
product 2i (0.5 h) in 72% yield (entry 9). The compound 1j
with a methoxy group at the p-position of the allene
functionality afforded the desired product 2j in 66% yield
(entry 10), and a satisfactory yield of 2k was also achieved
when the methylenedioxy derivative 1k was used (entry 11).
These two experimental results are obviously different from
those obtained by the reactions of 1d and 1e in which the
ring-closed products were obtained in rather low yields
(entries 4 and 5). The nitro derivative 1l efficiently (0.5 h)
provided the corresponding ring-closed product 2l in 80%
yield (entry 12). The unsubstituted allene 1m afforded the
benzo[f]oxyindole 2m, but the yield was fairly low (entry 13).
However, it is not a serious drawback to this newly developed
HPKTR. A phenylsulfonyl group can be regarded as a surro-
gate of hydrogen and be easily converted into a hydrogen
atom by conventional means.[14] In fact, the phenylsulfonyl
group attached to the aromatic ring of 2a was easily removed
by the reaction with tributyltin hydride in the presence of
AIBN and the subsequent acidic workup to furnish 2m in
85% yield (Scheme 3). In addition, it became apparent that
Scheme 5. Plausible mechanism for construction of 2 or 4 from 1 or 3,
respectively.
Route a, which is our working hypothesis, might be initiated
by isomerization of the nitrile group into the phenylketen-
imine F. The subsequent oxidative addition of the imine part
and the distal double bond of the allene functionality to RhI
would afford the rhodacycle intermediate G. The resulting
intermediate G would end up with the production of 2 or 4 by
successive insertion of CO and reductive elimination. The
phenylketenimine F may alternatively undergo the 6p-
electrocyclic reaction to furnish the naphthoazaquinodime-
thane H,[15] which might immediately be captured by RhI to
furnish G. Another possible route b involves the direct
oxidative addition of both the nitrile group and the distal
double bond of the allene functionality into RhI leading to the
formation of the rhodacycle intermediate I, which would
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collapse to the final products 2 or 4 by the insertion of CO,
reductive elimination, and aromatization.
11b in 32% yield. Lowering the reaction temperature to 808C
effected improvement of the yield (69%)[18] in this case
(Table 2, entry 2). The structure of 11b was unambiguously
confirmed by its X-ray crystallographic analysis.[19] The effect
of other electron-withdrawing groups was also investigated.
The ethoxycarbonyl derivative 10c was treated with the
rhodium(I) catalyst to produce 11c in 43% yield (entry 3),
and the phenylsulfonyl-substituted substrate 10d furnished
the cycloadduct 11d in similar yield (entry 4). The highest
yield (83%) was attained when the pivaloyl derivative 10e
was used (entry 5). The o- and p-nitrophenyl groups could
serve as weak electron-withdrawing functionalities in this
reaction, thus resulting in the formation of the azabicyclo-
[3.3.0] derivatives 11 f (16% yield) and 11g (37%), respec-
tively, with the recovery of the starting materials 10 f and 10g
(entries 6 and 7).
To confirm whether the reaction proceeded by the proton
tautomerization of the nitrile functionality, the dimethyl
derivative 5 was exposed to the standard reaction conditions
to furnish the indenopyrrole derivative 6[16,17] in 19% along
with a trace amount of the indene derivative 7, both of which
are obviously different from the expected [2+2+1] cyclo-
addition product 8 (Scheme 6). In addition, neither the
Since the nitrile group was found to be one of the two
suitable electron-withdrawing groups, several malononitrile
derivatives (12a–d) having other alkyl substituents on the
allenyl moiety were submitted to the reaction conditions
(Table 3). The methylallene derivative 12a smoothly under-
Scheme 6. Rhodium(I)-catalyzed ring-closing reaction of 5 and 9.
Table 3: [{RhCl(CO)dppp}2]-catalyzed HPKTR of 2-cyanohexa-4,5-diene-
nitriles (12).
benzonitrile 9a nor 9b afforded the desired carbonylative
products at all. Based on these three experiments, it might be
tentatively concluded that the transformation of 1 or 3 into 2
or 4, respectively, must occur through the initial isomerization
of the nitrile group into the intermediates F and/or H (route a
in Scheme 5).
We next examined the rhodium(I)-catalyzed carbonyla-
tive [2+2+1] cycloaddition of the aliphatic nitrile derivatives.
The hexa-4,5-dienenitrile 10a (R = H) was treated with
10 mol% [{RhCl(CO)dppp}2] for a prolonged time, but no
reaction occurred (Table 2, entry 1). We anticipated that
introduction of a suitable electron-withdrawing substituent at
the a position to the nitrile group of 10a would accelerate the
isomerization into the ketenimine form (e.g. intermediate F in
Scheme 5). Thus, the malononitrile derivative 10b was
refluxed in toluene to gratifyingly furnish the desired product
Entry
Substrate
R
t [h]
Yield [%]
1
2
3
4
12a
12b
12c
12d
Me
iPr
tBu
CH2OTBS
0.25
13a: 54
13b: 62
13c: 58
13d: 39
1
4
1
TBS=tert-butylsilyl.
went the carbonylative [2+2+1] ring-closing reaction
(entry 1), but the yield of the product 13a (54%) was lower
than that of the n-butyl derivative 11b (see Table 2, entry 2).
The sterically more-hindered isopropyl (12b) and tert-buty-
lallenes (12c) produced the corresponding azabicyclo[3.3.0]
derivatives 13b and 13c in acceptable yields (62% and 58%),
which are similar to that of 11b (Table 2, entry 2). The
functionalized siloxymethyl derivative 12d provided the
desired product 13d in a slightly lower yield (entry 4).
The pivaloyl substituent provided the highest yield in
a series of the n-butylallene substrates 10 (Table 2, entry 5).
However, this was not the case for the 4-alkyl-2-pivaloyl
derivatives 14a–c, in which the yields widely varied in the
range of 19 to 52% as shown in Table 4. Presumably, the fairly
bulkier pivaloyl group might decrease their reactivity.[20]
To further extend the scope of this method, the one-
carbon homologated malononitrile 16 was reacted with the
rhodium(I) catalyst to furnish two carbonylative azabicyclo-
[4.3.0] derivatives in a total 40% of yield (Scheme 7): 5-butyl-
6,7-dihydrooxyindole (17, 17%) and 5-butyloxyindole (18,
23%).[21] The azabicyclo[5.3.0]decadienone 20 could also be
formed from 19 using the procedure described above,
although the chemical yield was lower.
Table 2: [{RhCl(CO)dppp}2]-catalyzed HPKTR of hexa-4,5-dienenitriles
(10).
Entry
Substrate
R
T [8C]
t [h]
Yield [%]
[a]
1
2
3
4
5
6
7
10a
10b
10c
10d
10e
10 f
10g
H
CN
reflux
80
reflux
95
95
95
20
4
4.5
8
5
32
29
–
11b: 69
11c: 43
11d: 48
11e: 83
11 f: 16[b]
11g: 37[c]
CO2Et
SO2Ph
Piv
o-NO2C6H4
p-NO2C6H4
95
[a] No reaction took place. [b] The compound 10 f was recovered in 49%
yield. [c] The compound 10g was recovered in 23% yield.
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Soc. 2000, 122, 12663 – 12674; e) S. K. Mandal, S. R. Amin, W. E.
Table 4: [{RhCl(CO)dppp}2]-catalyzed HPKTR of 2-pivaloylhexa-4,5-
dienenitriles (14).
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Entry
Substrate
R
t [h]
Yield [%]
1
2
3
14a
Me
iPr
tBu
10
21
1
15a: 28[a]
15b: 19[b]
15c: 52
14b
14c[c]
[a] The compound 14a was recovered in 4% yield. [b] The compound
14b was recovered in 55% yield. [c] 20 mol% [{RhCl(CO)dppp}2] was
used at refluxing temperature.
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[10] Similar reaction conditions with AgBF4 afforded 1a in a rather
lower yield (17%). The cationic [{Rh(CO)dppp}2]Cl, which was
very effective in some cases of our PKTR of allenynes or
allenenes,[8] also furnished 2a in a low yield (22%). Neither
[RhCl(CO)(PPh3)2] nor [Mo(CO)6] was shown to be effective
for our purpose and only a complex mixture was formed. It has
already been shown that the rhodium(I)-catalyzed PKTR of
enynes under a low CO pressure occasionally provides better
results (see F. Inagaki, N. Itoh, Y. Hayashi, Y. Matsui, C. Mukai,
Scheme 7. Rhodium(I)-catalyzed ring-closing reaction of 16 and 19.
In summary, we developed the novel [{RhCl(CO)dppp}2]-
catalyzed intramolecular carbonylative [2+2+1] cycloaddi-
tion of 2-(1,2-propadienyl)phenylacetonitrile derivatives
under mild reaction conditions, thus leading to the facile
formation of benzo[f]oxyindole derivatives. Application of
this newly developed aza-Pauson–Khand-type reaction was
extended to aliphatic substrates. Namely, the 4-alkylhexa-4,5-
dienenitriles having an electron-withdrawing group at the
a position to the nitrile produced 2-azabicyclo[3.3.0]octa-
1(8),5-dien-3-ones in moderate yields. Thus, we could dem-
onstrate the usefulness of the nitrile functionality in the
carbonylative [2+2+1] cycloaddition reaction. The scope and
limitations of this method as well as application to the
synthesis of the natural products are now in progress.
Received: July 3, 2013
Published online: August 28, 2013
Keywords: allenes · cycloaddition · heterocycles · rhodium ·
.
synthetic methods
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Communications
Beilstein J. Org. Chem. 2011, 7, 404 – 409). Thus, we next
examined the effect of the CO pressure, but a yield better than
60% yield could not be achieved.
and 7 (CCDC 939921) were unambiguously confirmed by their
X-ray crystallographic analyses; see the Supporting information.
[17] The formation of 6 and 7 was rationalized based on the
mechanism proposed by Padwa and Yeske, and Martꢁn,
Ruano, and co-workers. See: a) A. Padwa, P. E. Yeske, J. Am.
Chem. Soc. 1988, 110, 1617 – 1618; b) A. Padwa, P. E. Yeske, J.
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[18] The reaction conditions, such as the rhodium(I) catalyst, solvent,
and addition of acid or base, were examined again using 10b in
anticipation of an easy isomerization to the ketimine form, but
all efforts were fruitless.
[19] CCDC 939922 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[20] The pivaloyl derivative 10e produced the 6-butyl-8-pivaloyl-2-
azabicylo[3.3.0] compound 11e in the highest yield. It is
uncertain about the reason so far, but other pivaloyl derivatives
14 having methyl, isopropyl, and tert-butyl groups tend to
produce the corresponding 6-alkyl-8-pivaloyl-2-azabicylo[3.3.0]
compound 15 in rather low yields compared to those of the 6-
alkyl-8-cyano-2-azabicylo[3.3.0] compound 13.
[11] The ring-closing reaction of 1a was performed under an
atmosphere consisting of 0.1 atm of CO and 0.9 atm of Ar
which unexpectedly produced 2a in a low yield (16%). Increas-
ing the CO pressure to 5 atm also led to a decrease in the
chemical yield (23%). When the reaction was carried out under
an atmosphere of CO with 5 mol% [{RhCl(CO)dppp}2], the
chemical yield of 2a decreased to 28%.
[12] The isomerization of nitrile to ketenimine species might be
accelerated by addition of base. Thus, the rhodium(I)-catalyzed
[2+2+1] cycloaddition of 1a was performed in the presence of
one equivalent of K2CO3 or iPr2NEt. However, no significant
improvement could be attained (yield of 2a: 24–40%).
[13] It was shown that 20 mol% of the rhodium(I) catalyst afforded
a better yield, but we used 10 mol% of the catalyst for the
following experiment.
[14] C. Nahera, M. Yus, Tetrahedron 1999, 55, 10547 – 10658.
[15] a) S. Kitagaki, K. Ohdachi, K. Katoh, C. Mukai, Org. Lett. 2006,
8, 95 – 98; b) S. Kitagaki, Y. Okumura, C. Mukai, Tetrahedron
Lett. 2006, 47, 1849 – 1852; c) S. Kitagaki, K. Katoh, K. Ohdachi,
Y. Takahashi, D. Shibata, C. Mukai, J. Org. Chem. 2006, 71,
6908 – 6914; d) S. Kitagaki, Y. Okumura, C. Mukai, Tetrahedron
2006, 62, 10311 – 10320.
[16] The compound 6 was converted into the corresponding tosylate
26 in 55% yield by conventional means (TsCl, iPr2NEt and
DMAP in CH2Cl2). The structures of both 26 (CCDC 939923)
[21] The oxyindole derivative 18 was tentatively regarded as an over-
oxidized product of 17. Thus, the compound 17 was exposed to
the rhodium(I) catalyst under the standard reaction conditions,
but no conversion into 18 could be observed and 17 was
recovered intact.
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Angew. Chem. Int. Ed. 2013, 52, 11138 –11142