Conformational, steric and electronic effects on the site- and chemoselectivity of the metal-catalyzed reaction of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides

Article abstract of DOI:10.1039/c2ob25103e

The Rh(ii)- and Cu(ii)-catalyzed reactions of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides are investigated to delineate how conformational, steric and electronic factors influence the site- and chemoselectivity of the metallocarbenoid r

Full text of DOI:10.1039/c2ob25103e

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PAPER
Conformational, steric and electronic effects on the site- and chemoselectivity
of the metal-catalyzed reaction of N-bis(trimethylsilyl)methyl, N-(2-indolyl)-
methyl α-diazoamides†
Bao Zhanga,b and Andrew G. H. Wee*a
Received 13th January 2012, Accepted 16th April 2012
DOI: 10.1039/c2ob25103e
The Rh(II)- and Cu(II)-catalyzed reactions of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl
α-diazoamides are investigated to delineate how conformational, steric and electronic factors influence the
site- and chemoselectivity of the metallocarbenoid reaction. The N-bis(trimethylsilyl)methyl (N-BTMSM)
group is found to be essential in promoting the metallocarbenoid reaction at the N-(2-indolyl)methyl
moiety as well as providing subtle but effective conformational influence about the amide N–Cα sigma
bond in diazoamides carrying an N–Cα alkoxymethyl side-chain, to afford excellent site- and
chemoselectivity. In general, the metal-catalyzed reactions are found to favor metallocarbenoid addition
to the indole C(2)–C(3) double bond over C–H insertion to give cyclopropanated products
(tetracyclic γ-lactams); however, chemoselectivity is also affected by steric effects, as revealed in the
N-[2-(3-methylindolyl)]methyl diazoamides, and to some extent by the nature of the catalyst
employed, as seen in the N–Cα-alkoxymethyl diazoamides. The tetracyclic γ-lactams are found to
rearrange to give good to high yields of the tricyclic indole derivatives under the metallocarbenoid
reaction conditions or under acidic conditions. The propensity of the tetracyclic γ-lactams to undergo
rearrangement is found to be dependent on the nature of the α-substituent on the original diazo carbon
and the indole N-substituent.
electrophilic aromatic substitution reaction2a is the most widely
Introduction
used method of introducing substituent groups into the indole
ring. In particular, Friedel–Crafts-type alkylation reactions,2b
The indole nucleus is an important structural motif found in
many naturally occurring usually biologically active compounds,
in therapeutically relevant molecules, and in agrochemicals.1
The synthesis of these molecules relies on the availability of
appropriately functionalized indole derivatives, which has engen-
dered intensive efforts directed at developing methods for the
functionalization of indoles. The most common functionalization
sites are at the indole nitrogen, C(2)- and C(3)-positions. The
promoted by homogeneous and heterogeneous Brønsted acids,
Lewis acids and, more recently, by organocatalysts2c (usually
amine-based catalysts), have received much attention. At the
same time, the metal-catalyzed functionalization of indoles is
also an area of intensive investigation, wherein Pd-catalyzed
reactions have featured prominently in these studies.3
The metal-catalyzed reaction of indoles with α-diazocarbonyl
compounds is a useful method for the introduction of substitu-
ents into the indole nucleus.4 Both inter- and intramolecular
reactions have been explored. The metal-catalyzed intermolecu-
lar reaction of indole and its derivatives with α-diazocarbonyl
compounds in the presence of either copper [e.g. Cu bronze, Cu-
(acac)2, Cu(OTf)2] or Rh(II) [e.g. Rh2(OAc)4, Rh2(S-DOSP)4]
catalysts has been extensively investigated, and several character-
istics have been noted. It is generally found that products arising
from C(3) alkylation are preferred over C(2) alkylation,5 but the
latter products are formed if the indole C(3) is substituted.6
Indole N–H insertion to give N-alkylated products is found to be
in competition with C-alkylation, but the formation of N-alky-
lation products is also dependent on the type of α-diazocarbonyl
compound and catalyst that are used.7 An interesting exception
aDepartment of Chemistry and Biochemistry, University of Regina,
Regina, Saskatchewan, Canada, S4S0A2. E-mail:
andrew.wee@uregina.ca; Fax: +1 306 337 2409
bSchool of Chemical Engineering and Technology, Tianjin University,
Tianjin 300072, China. E-mail: baozhang@tju.edu.cn
†Electronic supplementary information (ESI) available: Experimental
procedures and data for 6a,b; 7a–c; 8a–c; 9a–d, 10a–h, 18c, 18e, 18f
(20f), 18g, 19d, 19g, 19h, 20c–e, 22a–c, 23a–e, 26, 27, 29, 30a–c,
31a–d, 32b,d, 33b 34, 36, 39, 40, 41b. Copies of 1H and 13C NMR
spectra for compounds 10–17, 18c, 18e, 18f (20f), 18g, 19d,g,h, 20c–e,
22a–c, 23a–d, 24a, 24c (25c), 24e, 25a, 26, 27, 29, 30a–c, 31a,c, 32b,
d, 33b, 34, 36, 39, 40 and 41b; crystallographic data and CIF files for
compounds 19h and 34. CCDC 691157 and 863240. For ESI and crys-
tallographic data in CIF or other electronic formats see DOI: 10.1039/
c2ob25103e
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to this trend has been observed recently wherein a Ru(II)-cata-
lyzed reaction of indole with α-diazoarylacetates selectively gave
the C(2) alkylation product, and N-alkylation products were not
detected.8 For indoles with an N-electron withdrawing group
(e.g. Ac, Aroyl, Boc), stable cyclopropanecarboxylate intermedi-
ates were obtained by reaction with ethyl or methyl diazoacetate
catalyzed by copper.9 Interestingly, double cyclopropanation of
the benzene unit of the indole was observed when N-Boc-2 (or
3)-methylindole was treated with methyl α-diazo-(4-bromophe-
nyl)acetate, a donor–acceptor diazocarbonyl compound, in the
presence of Rh2(S-DOSP)4 as the catalyst.10
The formation of C-alkylation products is generally believed
to follow a pathway involving cyclopropanation and ring scis-
sion of the unstable cyclopropane intermediates;6b,c,8 however,
there is also evidence which supports a pathway involving
zwitterionic intermediates.5,10
respectively. In these latter cases, unstable cyclopropyl inter-
mediates were formed, which underwent in situ intramolecular
ring-opening by the NHTs (Ts = tosyl) unit to give 5.
In comparison, the metal-catalyzed intramolecular reaction of
an indole or its derivatives with an α-diazo tertiary amide
moiety tethered to C(2) has not been examined yet. This may be
due, in part, to regio- and chemoselectivity issues arising from
conformational preferences about the amide N–C(O) unit, which
can result in product mixtures and poor yields. Therefore,
control of site-selectivity in the metallocarbenoid reaction is an
important consideration in this type of reaction, with the aim of
promoting metallocarbenoid attack at only one of the two N-
substituents.12
One such strategy used to improve site-selectivity involved
replacing one of the N-substituents of the α-diazo tertiary amide
moiety with a bulky group (e.g. tert-butyl, neopentyl, 4-methoxy-
phenyl, 2,4,6-trimethylbenzyl, cumyl),13 which sterically
biases the conformational preference about the amide N–C(O)
moiety in favor of the metallocarbenoid reaction at the remaining
N-substituent. Another strategy involves the use of an N-substi-
tuent that is electronically deactivated, such as N-(4-nitrophe-
nyl), N-(carbalkoxyethyl) or N-(benzylchromium tricarbonyl),
so that the metallocarbenoid reaction will be directed toward the
remaining electron-rich N-substituent.14 However, there are
some limitations noted for these two approaches. For example,
the N-tert-butyl group is susceptible to metallocarbenoid C–H
insertion at one of the methyl groups, and is not easy to remove
from the lactam products.15 For the N-PMP group, we have
found16 that, in cases where the Rh(II)-carbenoid C–H insertion
at the second N-substituent was difficult, due to electronic de-
activation and/or steric hindrance at the reaction site, the Rh(II)-
carbenoid had preferentially attacked the N-PMP group leading
to the formation of oxindole derivatives.
The intramolecular version, in contrast, has received less atten-
tion, and most of the studies11 reported to date involve a metal-
catalyzed reaction of indole and its derivatives with diazocarbo-
nyl moieties tethered mainly to the indole-C(3) position. For
example, Salim and Capretta,11a and Muchowski and co-work-
ers11b independently reported the Rh(II)-catalyzed intramolecular
reaction of 3-indolyl α-diazoketones wherein formal metallocar-
benoid C–H insertion at the indole-C(2) position was observed.
Subsequently, Jung described the Rh(II)-catalyzed intramolecular
reaction of indole derivatives with a tethered α-diazo ketoester
unit at the C(3) position,11c which resulted in the formation of
tricyclic β-keto esters. In all these examples, the involvement of
an unstable cyclopropyl intermediate was implicated enroute to
the formation of the tricyclic products; in one case, the interme-
1
diacy of a cyclopropyl derivative was observed by H NMR.11a
However, in the case of the Cu(I)-catalyzed intramolecular reac-
tion of an indole derivative bearing a C(3)-tethered ‘donor–
acceptor’-type diazoamide moiety,11d a stable cyclopropyl inter-
mediate was isolated.
We previously reported17 that the metallocarbenoid mediated
reaction of N-bis(trimethylsilyl)methylamine (N-BTMSM) di-
azoamides proceeded efficiently with good to excellent regio-
and chemoselectivity and had attributed the latter results to the
conformational control about the amide N–C(O) bond that was
afforded by the N-BTMSM moiety. Furthermore, we also noted
another role, albeit subtle, that the N-BTMSM group had played
in influencing the conformational preference about the amide N–
Cα sigma bond in systems carrying two substituents at the
carbon α to the amide nitrogen (hereafter referred to as N–Cα-
branched). To further explore the scope of the metallocarbenoid
reactions of N-BTMSM diazoamides, we have investigated the
reaction of N-BTMSM, N-(2-indolyl) diazoamides. We were
interested in determining: (a) the effectiveness of the N-BTMSM
group as a conformational control element in these systems and
(b) the influence of electronic effects of: (i) the α-substituent on
the carbenoid carbon, (ii) the indole N-substituent and (iii) the
metal catalysts on the regio- and chemoselectivity in the reaction.
Here, we detail the results from our studies.18
ð1Þ
Studies on the metal-catalyzed intramolecular reaction of
indoles possessing a C(2)-tethered diazocarbonyl moiety have,
so far, been limited. Salim and Capretta showed11a that the
metal-catalyzed intramolecular reaction of the α-diazoketone 1
gave mainly the N–H insertion product 2 (70%); the tricyclic
ketone 3 (25%), formed from a formal metallocarbenoid C(3)–H
insertion, was a minor product (eqn (1)). Recently, Qin and co-
workers reported11e the Cu(I)-catalyzed intramolecular reaction
of the α-diazoketone 4a and α-diazo β-ketoester 4b, which led to
the formation of the tetracycles 5a (42%) and 5b (81%),
We have found that the use of the N-BTMSM moiety was
essential for encouraging the metallocarbenoid reaction to occur
mainly at the indolyl moiety via its conformational influence on
the amide unit in both N–Cα-unbranched and N–Cα-branched
systems. Our results indicate that in the present system, the
cyclopropanation pathway is followed even when the C(3) pos-
ition of the indolyl unit is substituted. The cyclopropyl
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intermediates were generally stable and amenable to isolation,
but in some cases rearrangement of the tetracyclic γ-lactams to
give the tricyclic products under the metallocarbenoid reaction
conditions was observed.
reduction gave better yields of 9b–d compared to a one-pot
procedure.
Acylation of the N-BTMSM amines 9a–d with either methyl
or ethyl diazomalonyl chloride17b,22 gave the diazoamides 10a–d
in good yields (70–80%). The α-acetyl substituted diazoamides
10e,f were obtained via treatment of 9c,d with diketene followed
by the diazotization of the resulting crude acetoacetamides17c
23
with MsN3 (71–79% yield over two steps). Subsequent deacy-
Results and discussion
lation of 10e,f, using 5% aq KOH in MeCN, gave the diazo-
amides 10g,h in yields ranging from 81–90%.
The chemistry of the N-BTMSM, N-(2-indolyl) diazoamides 10
was first investigated and they were readily prepared from 2-
indolylmethylamines 9 as shown in Scheme 1. The known19a N,
O-dimethyl-2-indolecarboxamide 6c was subjected to N-phenyl-
sulfonylation19b (PhSO2Cl, KOBu-t, cat. 18-C-6) and N-methy-
lation19c (MeI, NaH) to provide amides 6a and b,19d
respectively. Reduction of 6a–c with LiAlH4 at −78 °C gave the
corresponding 2-indolecarbaldehydes 7a,20a 7b,20b and 7c,20c
which were then subjected to reductive amination to obtain
amines 9. Thus, one-pot reductive amination21 of 7a with ethyl-
ammonium chloride gave 9a. For the preparation of the N-bis(tri-
methylsilyl)methylamine (N-BTMSM) derivatives 9b–d it was
found that condensation of 7a–c with (TMS)2CHNH2 to form
the stable N-BTMSM imines, 8a–c, followed by NaBH4
Metal-catalyzed reaction of N-BTMSM indolyl diazoamides 10
Studies of the metal-catalyzed reactions began with compounds
10a (eqn (2)) and 10b (eqn (3)). For diazoamide 10a the derived
Rh(II)-carbenoid can, in principle, be involved in (i) a formal
C–H insertion reaction at the indole-C(3) position, resulting in a
tricyclic product, (ii) C–H insertion reaction at the indolylmethy-
lene position to form a β-lactam, and (iii) at the N-ethyl group to
form β- and γ-lactam products. In the case of 10b, the Rh(II)-car-
benoid can also react at the indolic N–H site in addition to the
indolylmethyl moiety and N-BTMSM methine and one of the
SiMe3 groups. Therefore, a comparison of the results from these
two reactions should allow an assessment of whether the N-
BTMSM group is effective in influencing the site-selectivity in
the reactions of the diazoamides.
ð2Þ
The exposure of 10a24a to Rh2(OAc)4 gave (73% combined
yield) the readily separable tetracyclic γ-lactam 11, the γ-lactam
12 and the β-lactam 1324b in a ratio of 2 : 2.2 : 1 (eqn (2)). Com-
pound 11 had resulted from metallocarbenoid addition to the
indole C(2)–C(3) double bond, and the two lactams 12 and 13
were formed via Rh(II)-carbenoid insertion into the methyl and
methylene units of the N-ethyl moiety. More interestingly, the
results indicated that the preferred reaction site for the metallo-
carbenoid was at the N-ethyl unit, as reflected by the higher com-
bined yield of 12 and 13 (44%), compared to a yield of 28% for
11. Furthermore, cyclopropane ring scission of the tetracyclic
γ-lactam 11 occurred to give the tricyclic indole derivative 14
Scheme 1 Preparation of diazoamides 10a–h.
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Table 1 Rh(II)- and Cu(II)-catalyzed reactions of diazoamides 10c–ha
when a CDCl3 solution of 11 was left to stand at room tempera-
ture for 24 h.
ð3Þ
Next, the Rh2(OAc)4-catalyzed reaction of N-BTMSM diazo-
amide 10b was studied (eqn (3)). Interestingly, in this case, the
tricycle 15 was formed as the major product in 65% yield.
Although the reactive Rh(II)-carbenoid had the opportunity to
insert into the indole N–H bond to form the pyridazine deriva-
tive 17, its isolated yield was only 8%. In fact, the formation of
β-lactam 16 was preferred over 17. The other product that was
formed was the imine 8a (10%) which was derived via a
hydride-transfer based mechanism.12b,25 It is noteworthy that
there were no products arising from Rh(II)-carbenoid C–H inser-
tion at the N-BTMSM methine or at the methyl of one of the
SiMe3 groups.
Together, the results from the reaction of 10a (eqn (2)) and
10b (eqn (3)) provided strong support for the notion that the N-
BTMSM group is effective in influencing the conformational
preference about the amide N–C(O) unit. Thus, for 10b, it is
reasonable to suggest that the preferred reaction conformer corre-
sponds to the one where the larger N-BTMSM substituent is
located syn to the less sterically demanding amide carbonyl
group, and the smaller indolylmethyl moiety is oriented towards
the reactive Rh(II)-carbenoid (Fig. 1).
Relative yieldc (%)
Entry
Diazo 10
Catalyst
Yieldb (%)
18
19
20d
1
2
3
4
5
6
7
8
c
c
c
c
d
d
d
e
f
Rh2(OAc)4
Rh2(tfa)4
Cu(hfacac)2
Cu(acac)2
Rh2(OAc)4
Rh2(tfa)4
Cu(hfacac)2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
89
73
78
87
79
60
61
40
41
95
87
100
86
100
100
0
0
0
50
27
0
0
0
0
0
75
53
100
0
0
100
100
0
14e
0
0
25f
47g
0
50f
73f
0
9
10
11
g
h
0
0
a 2 mol% Rh(II) or 4 mol% Cu(II) catalyst, dry CH2Cl2, rt. b Combined
yield of 18, 19, 20. c The imine product 8b or c was also obtained: entry
1: 8% 8b; entry 2: 6% 8b; entries 3 and 4: 8b not detected; entry 5:
<1% 8c; entry 6: 8% 8c; entry 7: 8c not detected; entry 8: 21% 8b;
entry 9: 7% 8c; entries 10 and 11: 8b,c not detected. d The relative
stereochemistry at C(3) and C(4) was assigned based on the Jvic: for the
cis-diastereomer, JH-3,H-4 = 2.2 Hz; for the trans-diastereomer, JH-3,H-4
=
Informed by the results from the reactions of 10a,b, we sub-
jected the other N–Cα-unbranched diazoamides 10c–h to differ-
ent Rh(II) and Cu(II) catalysts with the aim of defining how
electronic effects from the N-substituted indole ring, the α-sub-
stituent on the metallocarbenoid carbon and the nature of the cat-
alysts would influence the chemoselectivity of the reaction. The
results from this study are shown in Table 1.
5.7 Hz. e cis-Diastereomer. f trans-Diastereomer. g cis : trans = 1 : 1
based on the weight of the isolated products.
In general, the preferred reaction pathway for the reactive
metallocarbenoid is addition to the indole C(2)–C(3) double
bond to give either the tricyclic indole derivative 18 or the tetra-
cyclic γ-lactam 19.26 Metallocarbenoid insertion into the indolyl-
methylene C–H bond to form the β-lactam 20 represented the
only competitive pathway. In some of the reactions, a minor
amount of the imines 8b or c (with the exception of 10e, entry
8) was also obtained (Table 1, footnote c), whose formation
appeared to be dependent on the starting diazoamide structure
and the nature of the catalyst; imines 8b,c tend to be formed
when Rh(II) catalysts are used but not with Cu(II) catalysts.
The influence of the indole N-substituent and the type of cata-
lyst on the chemoselectivity of the reaction was revealed in the
reactions of the diazomalonamides 10c,d. Thus, the Rh2(OAc)4-
catalyzed reaction of 10c resulted in Rh(II)-carbenoid cyclopro-
panation of the indole C(2)–C(3) double bond followed by in
situ ring opening of the cyclopropyl moiety to give the tricycle
18c in 89% yield (entry 1). No β-lactam product 20c was
Fig. 1 Conformational preference about the N-BTMSM amide unit in
10b.
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detected. The use of the more electrophilic Rh2(tfa)4 catalyst, on
the other hand, led to an erosion of chemoselectivity (entry 2);
although the tricyclic product was still obtained as the major
product, there was a significant increase in the yield of the
β-lactam 20c. Interestingly, it was found that both the Cu-
(hfacac)2 and Cu(acac)2-catalyzed reactions of 10c gave only
18c. The nature of the ligand on the Cu(II) complex was found to
have little effect on the chemoselectivity of the reaction except
on the yield of 18c; a higher yield of 87% was realized with Cu-
(acac)2 compared to a yield of 78% with Cu(hfacac)2.
Unexpectedly, 19g did not undergo rearrangement to the tricyclic
indole derivative 18g under the metallocarbenoid reaction con-
ditions. This outcome, when considered together with the result
from the reaction of 10c, suggests that an electron-donating
indole N-substituent works in concert with an electron-withdraw-
ing group at C(3a) of the tetracyclic γ-lactam (e.g. 19c) to facili-
tate the rearrangement to the tricyclic product. However, it
should be noted that a CDCl3 solution of 19g, like 11 (eqn (2))
was also found to rearrange to the tricycle 18g upon standing at
room temperature for 22 h.
The composite results from the reactions of the α-diazomalo-
namides 10c,d showed several useful trends. The formation of
the tricycle 18 and the tetracyclic γ-lactam 19 is found to be
dependent on the nature of the indole N-substituent. Cyclopropyl
ring opening of the initially formed 19 to give 18 under the reac-
tion conditions is facilitated by an electron-donating indole N-
methyl substituent, whereas an electron-withdrawing N-PhSO2
group afforded stability to the tetracyclic γ-lactam 19.
Rh(II)-carbenoid reaction of diazoamides 23a,c,e
The interesting results from the reactions of diazoamides 10c–h
led us to investigate whether the chemoselectivity of the reaction
would also be affected by steric hindrance at the indole C(2)–C
(3) double bond. Steric hindrance at this site could divert metal-
locarbenoid attack away from the double bond and towards the
indolylmethylene site, resulting in higher yields of β-lactam
products.
For this study, the 3-methylindolyl diazoamides 23a,c,e were
prepared. Their synthesis began with the preparation of amines
22a,c as shown in Scheme 2. The known27a 2,3-dimethyl-1-
(phenylsulfonyl)indole was treated with NBS (cat. benzoyl per-
oxide) to give crude bromide 2127b which, without further purifi-
cation, was reacted with (TMS)2CHNH2 to afford the crude
amine 22a (59% yield over 2 steps). Amine 22c was prepared
via base mediated hydrolysis of the N-PhSO2 group in 22a to
form 22b, followed by regioselective indole N-methylation. With
22a,c in hand, the diazoamides 23a,c,e were prepared in the
same manner as was described for the preparation of the diazo-
amides 10d,g,h (vide supra). We found, however, that the diazo-
amide 23e was unstable and therefore was used immediately
after purification.
It is also evident that the nature of the indole N-substituent
has an important influence on the chemoselectivity of the reac-
tion. For example, the Rh(II)-catalyzed reaction of diazoamide
10c occurred with high chemoselectivity to give the tricyclic
product 18c as the predominant product, whereas with diazo-
amide 10d significant amounts of the β-lactam 20d were
obtained (compare entries 1 and 5). A reasonable explanation for
the change in the degree of chemoselectivity is the decreased
reactivity of the indole C(2)–C(3) double bond. When the indole
N-substituent is methyl, this double bond is activated towards
metallocarbenoid cyclopropanation to give the tetracyclic
γ-lactam 19, which subsequently rearranges to give the tricycle
18. However, with an electron-withdrawing indole N-PhSO2
group, the reactivity of the indole C(2)–C(3) double bond is
decreased, and consequently C–H insertion at the indolylmethy-
lene site to form β-lactam 20 becomes a competitive reaction
pathway. The use of the electron-withdrawing Rh2(tfa)4 pro-
moted the formation of β-lactam 20 and this may be attributed to
the increased electrophilicity of the Rh(II)-carbenoid, resulting in
lower chemoselectivity (entries 2 and 6). Interestingly, the Cu(II)
catalyzed reaction of 10c,d displayed the same chemoselective
preference for the indole moiety (entries 3, 4, 7).
The results from the Rh2(OAc)4-catalyzed reaction of diazo-
amides 23a,c,e are collected in Table 2. Diazoamide 23a reacted
to give the tetracyclic γ-lactam 24a and β-lactam 25a in 81%
On the basis of the results from the reactions of 10c,d we
chose to use Rh2(OAc)4 as the catalyst in the reactions of 10e–h.
With 10e,f, lower chemical yields of 18e,f and 20e,f were
obtained (entries 8 and 9). Unexpectedly, in the case of 10e, sig-
nificant amounts of imine 8c were also formed, whose yield
(21% isolated) equalled that of the β-lactam 20e. The chemo-
selectivity of the reaction of 10e,f was also found to be poorer;
the ratio of 18e : 20e was 1 : 1 for 10e and 1 : 3 for 10f. The pro-
ducts 18e,f and 20e,f, especially the former, were found to be
somewhat unstable, and purification by chromatography always
resulted in low recovery of products due to decomposition on the
column. Also, slow degradation of the product was experienced
upon isolation and storage.
For the α-unsubstituted diazoamides 10g,h (entries 10, 11),
the Rh2(OAc)4-catalyzed reaction led only to the tetracyclic
γ-lactams 19g,h, in high yields. These results also indicate that
metallocarbenoid addition to the indole C(2)–C(3) double bond
is highly favored, irrespective of whether the indole nitrogen
carries an electron-donating or electron-withdrawing group.
Scheme 2 Preparation of diazoamides 23a,c,e.
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Table 2 Rh(II)-catalyzed reaction of diazoamides 23a,c,ea
Fig. 2 Potential Rh(II)-carbenoid reaction sites in 28.
tetracyclic γ-lactam and β-lactam products, 23a gave a lower
yield (67% combined) compared to 10d (79% combined) but, in
the case of 23a, the imine product 26 (R = PhSO2) was also
formed in significantly higher amounts (16%). However, the che-
moselectivity of the reaction, as reflected by the ratio of the tetra-
cyclic γ-lactam to β-lactam products, was very similar for 23a
and 10d. In the case of 23c and 10h, there is a difference in
product outcome: for 23c, the β-lactam 25c and the imine 26
(4%) were formed along with the tetracycle 24c, whereas for the
reaction of 10h, no β-lactam and imine products were produced.
A reasonable explanation for this is that in 23c the approach of
the electrophilic Rh(II)-carbenoid to the indole C(2)–C(3) double
bond may be hindered by the C(3)-methyl group, and conse-
quently the metallocarbenoid insertion at the indolylmethylene
group leading to the β-lactam 25c, and hydride abstraction to
form imine 26, occurred at the expense of cyclopropanation of
the indole C(2)–C(3) double bond.
Relative yield
(%)
Entry
Diazo 23
Yieldb (%)
24
25
1
2
3
ac
cc
e
67
72
73
81
75
100
19d
25
0
a 2 mol% Rh(II) catalyst, dry CH2Cl2, rt. b Combined yield of 24 and 25.
c The imine 26 was obtained for the reaction of 23a and c: entry 1 : 16%;
entry 2 : 4%. d The relative stereochemistry at C(3) and C(4) was
assigned based on Jvic: for the cis-diastereomer, JH-3,H-4 = 2.5 Hz; for
the trans-diastereomer, JH-3,H-4 = 5.7 Hz.
As was observed before for the tetracyclic γ-lactams 11 and
19g, a CDCl3 solution of 24e, upon standing at rt for 48 h, was
converted to a new compound, identified as the tricyclic product
27. The IR spectrum of 27 showed the characteristic δ-lactam v
(CvO) at 1630 cm−1, whereas in the precursor 24e, the carbonyl
1
absorption appeared at 1664 cm−1. In the H NMR spectrum,
and 19% relative yields, respectively. Compound 25a was
obtained as an inseparable mixture of cis- and trans-diastereo-
mers,24b and in a ratio of 1 : 3 based on the integration of the
C(4)–H doublet of the cis isomer (δ 4.42, JH-3,H-4 = 2.5 Hz) and
of the trans isomer (δ 4.20, JH-3,H-4 = 5.7 Hz). The reaction of
23c gave an inseparable mixture of 24c and 25c in a 72% com-
bined yield; the ratio of 24c : 25c was 3 : 1, which was based on
the integration of the doublet due to one of the C(1)–hydrogens
centered at δ 4.81 in the tetracyclic γ-lactam 24c and one of the
double doublets due to one of the C(3)–Hs centered at δ 3.27 in
β-lactam 25c. For the reaction of 23a and c, the imine product
26 was also obtained (see footnote c, Table 2). With 23e, only
the tetracyclic γ-lactam 24e was formed in 73% yield.
the characteristic signals at δ 3.55 (dd) and δ 3.80 (d) due to the
C(1)–methylene hydrogens in 24e were replaced by a broad
singlet at δ 5.22–5.32, which was ascribed to the C(1)–olefinic
proton.
Metal-catalyzed reaction of N–Cα-branched N-BTMSM indolyl
diazoamides
The site-selectivity studies on the metallocarbenoid reactions of
diazoamides 10a–h showed that the N-BTMSM group provides
useful and effective conformational control about the amide
bond, thereby favoring the metallocarbenoid reaction at the indo-
lylmethyl unit. Nonetheless, it is not clear whether this confor-
mational control will be operative in N–Cα-branched
diazoamides wherein the α-branch substituent may interfere with
conformational preferences, resulting in poor site selectivity. We
therefore prepared diazoamides of type 28 to ascertain whether
conformational influence about the N–Cα single bond by the N-
BTMSM moiety is possible. In system 28 (Fig. 2), there are
three potential competing sites for the metallocarbenoid reaction:
(i) at the indole C(2)–C(3) double bond (path a), (ii) at the
methylene C–H bonds adjacent to the methoxymethyleneoxy
(O-MOM) group (path b) and (iii) at the tertiary α-C–H bond in
the indolylmethine group (path c). It is, therefore, of interest to
determine which pathway will be preferred and how confor-
mational and electronic factors govern the chemoselectivity of
the reaction in diazoamides 28.
The structures of the tetracyclic γ-lactams 24a,c,e were readily
characterized based on analysis of the diagnostic 1H NMR
signals of the C(1)–Ha,Hb and C(3a)–Hc.26
Interestingly, the effect of the metallocarbenoid α-substituent
(CO2Et vs. H) on the chemoselectivity of the reaction of diazo-
amides 23a and 23c was minimal, as both reactions afforded
very similar ratios of tetracyclic γ-lactam 24 to β-lactam 25.
However, with the α-unsubstituted diazoamides 23c and e, a
marked difference in chemoselectivity was observed and this can
be attributed to a difference in the electron density of the indole
ring as noted earlier (vide supra).
It is also instructive to compare the results obtained from the
Rh2(OAc)4-catalyzed reactions of 23a and 23c to those from the
reactions of 10d (Table 1, entry 5) and 10h (Table 1, entry 11),
respectively. From the standpoint of the combined yield of the
4602 | Org. Biomol. Chem., 2012, 10, 4597–4608
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Table 3 Rh(II)- and Cu(II)-catalyzed reactions of diazoamides 31b,da
Relative yieldc (%)
Entry
31
Catalyst
Yieldb (%)
32
33d,e
1
2
3
4
5
6
b
b
b
b
d
d
Rh2(OAc)4
Rh2(cap)4
Rh2(tfa)4
Cu(hfacac)2
Rh2(OAc)4
Rh2(cap)4
98
91
69
85
80
93
82
91
57
59
100
100
18f
9f
43g
41h
0
Scheme 3 Preparation of diazoamides 31b,d.
0
a 2 mol% Rh(II) or 4 mol% Cu(II) catalyst, dry CH2Cl2, rt. b Yield of
chromatographically pure products. c The relative yield was calculated
based on the weight ratio of the isolated products. d γ-Lactam 33b was
obtained as separable cis- and trans-diastereomers. e The relative
stereochemistry at C(4) and C(5) was assigned based on Jvic: for the cis-
diastereomer, JH-4,H-5 = 8.5 Hz; for the trans-diastereomer, JH-4,H-5 = 0
Synthesis and metal-catalyzed reaction of diazoamides 31b,d
The propargylamine 29 was subjected to a Pd(II)-catalyzed reac-
tion with 2-iodo-N-(methanesulfonyl)aniline,28 to effect a one-
pot Sonogashira coupling and cyclization29a to obtain the indole
amine29b 30a in 72% yield (Scheme 3). It is useful to note that
the reaction proceeded quite efficiently without the need for pro-
tection of the N-BTMSM amino moiety. Subsequent base
hydrolysis of the N-MeSO2 group gave the indole amine 30b,
which was selectively protected at the indole nitrogen with
MOMCl to obtain amine 30c. The conversion of 30a,c to the
diazoamides 31b,d employed procedures similar to those
described for the preparation of diazoamides 10g,h and 23b,c
(vide supra) except for the acylation step with diketene.
f
Hz. The ratio of cis : trans was 1 : 1. g The ratio of cis : trans was 1 : 2.
h Only the trans-diastereomer was obtained.
indole double bond in 31b, due to the electron-withdrawing N-
MeSO2 group, allowed γ-lactam formation, via metallocarbenoid
C–H insertion at the oxymethylene group, to be competitive.
The lack of β-lactam formation, which would arise from C–H
insertion at the indolylmethine unit, can also be ascribed to pre-
ferential insertion at the oxymethylene moiety.
For the reaction of 31b, it was found that with the three Rh(II)
catalysts, a mixture of separable cis- and trans-33b was formed,
but with Cu(hfacac)2 only trans-33b was obtained. The relative
stereochemistry at C(4) and C(5) in 33b was assigned based on
For this step, the reaction was conducted in THF under reflux,
as the reaction was found to be slow at rt. The crude acetoaceta-
mide derivatives were then diazotized to provide the correspond-
ing α-diazo acetoacetamides, which were deacylated to give the
diazoamides 31b,d in 70% and 75% overall yields, respectively.
Diazoamides 31b,d were found to be less stable relative to the
unbranched diazoamides 10g,h and 23b and, therefore, were
used immediately after purification by chromatography.
We first studied the metal-catalyzed reaction of 31b and the
results are summarized in Table 3. Both Rh2(OAc)4 and the less
electrophilic Rh2(cap)4 (entries 1 and 2) provided high chemo-
selectivity wherein the tetracyclic γ-lactam 32b is favored over
the γ-lactam 33b. Chemoselectivity, however, was poor with the
strongly electron-withdrawing Rh2(tfa)4, which gave a 1.3 : 1
ratio of 32b : 33b (entry 3). A similar outcome (32b : 33b =
1.4 : 1) was also realized with Cu(hfacac)2 (entry 4).
1
the H NMR data. For trans-γ-lactam 33b, the vicinal JH-4,H-5
was found to be ∼0 Hz, which suggested that the dihedral angle
between the C(4)–H and C(5)–H was close to 90° and that these
hydrogens were trans to each other, whereas for cis-33b, JH-4,H-5
was 8.5 Hz.
ð4Þ
On the other hand, the Rh2(OAc)4- and Rh2(cap)4-catalyzed
reactions of N-(methoxymethyl) diazoamide 31d proceeded
efficiently and with excellent chemoselectivity (entries 5 and 6)
to give only the tetracyclic γ-lactam 32d.
The overall results above indicated that for the reactions of
31b,d, metallocarbenoid cyclopropanation of the indole C(2)–
C(3) double bond was generally preferred. Deactivation of the
In order to further confirm the tetracyclic structure of the
cyclopropanated product, we decided to recrystallize compound
32b for X-ray crystallographic analysis, since this product was
obtained as a crystalline compound; however, attempts to obtain
a single crystal of 32b failed. Fortuitously, the primary alcohol
34, obtained via treatment of 32b with acidic methanol at 60 °C
(eqn (4)), was highly crystalline and afforded a single crystal for
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Fig. 3 ORTEP drawing of 34.
Scheme 4 Acid-catalyzed rearrangement of 32d to 36.
under the metallocarbenoid reaction conditions can be related to
the indole N-substituent and the nature of the substituent on the
diazoamide α-carbon. Thus, tetracyclic γ-lactams derived from
indoles bearing an electron-withdrawing N-PhSO2 or N-MeSO2
group were generally more stable (except for 10f with an
α-acetyl group) whereas tetracyclic γ-lactams derived from
indoles possessing an electron donating N-Me or N-MOM group
are stable only when an electron-withdrawing substituent is
absent at C(3a). Obviously, relief of ring strain and aromatization
of the indole are not sufficient driving forces for rearrangement.
Furthermore, it was found that the stability of tetracyclic
γ-lactams to the acidic conditions is also related to the indole N-
substituent and the nature of the substituent on the diazoamide
α-carbon.31
We therefore investigated the rearrangement of 32d with the
aim of achieving a tandem selective indole N-MOM deprotec-
tion–rearrangement. Thus, treatment of 32d with catalytic
amounts of 6 M HCl in the presence of silica gel in CHCl3
nicely effected selective hydrolysis of the indole N-MOM group
and rearrangement of the tetracycle to the tetrahydro-β-carboline
36 in 84% yield (Scheme 4). A likely mechanism for the
rearrangement would involve a “push–pull” mechanism wherein
protonation of the lactam carbonyl oxygen in 32d initiates a
selective cleavage of the indoline N-MOM group and rearrange-
ment to the indolenine (or indolenium) intermediate 37, which
aromatizes to the enol intermediate 38 followed by tautomeriza-
tion to product 36.
To gain additional insight into the factors that can influence
the ring opening process, we investigated the BF3·OEt2-cata-
lyzed rearrangement of the stable tetracyclic γ-lactams 19h, 39
and 40 (Scheme 5). We reasoned that coordination of BF3·OEt2
to the lactam carbonyl should render this unit more electron-
withdrawing and thus facilitate the tetracyclic γ-lactam to the tri-
cycle rearrangement.
The treatment of 19h with 20 mol% BF3·OEt2 in 1,2-dichloro-
ethane (DCE), either at rt or 80 °C, did not give the expected tri-
cyclic indole derivative 41a, but only returned the starting
material 19h. Interestingly, no products that could have resulted
from desilylation of the N-BTMSM group were detected. The
unexpected inertness of 19h towards BF3·OEt2 led us to consider
Fig. 4 Preferred conformation about the N–Cα bond of the Rh(II)-
carbenoid from 31b,d.
X-ray crystallographic analysis. The X-ray structure of 3430 (Fig. 3)
clearly shows that the cyclopropyl moiety and the hydroxymethy-
lene group are located on opposite sides of the indoline ring.
The results shown in Table 3 suggest that the N-BTMSM
group not only provides conformational control about the amide
unit but can also exert an influence on the conformational prefer-
ence about the N–Cα sigma bond. On the basis of the preferred
conformation about the amide N–C(O) bond afforded by the
N-BTMSM moiety (Fig. 1, vide supra), the reaction of diazo-
amides 31a,b is envisaged to proceed via the equilibrating reac-
tion conformers 35 and 35′ (Fig. 4), which have resulted from
rotation about the N–Cα sigma bond.
The formation of 32 and 33 can be understood if we con-
sidered the reactive conformers 35 and 35′ of the Rh(II)-carbe-
noid intermediate (Fig. 4). In conformer 35, steric interaction
between the MOMOCH2 substituent and one of the TMS units
of the N-BTMSM group is present, and for 35′ there is steric
interaction between the indolyl moiety and the TMS group. It is
plausible that the indolyl group–TMS interaction in 35′ is more
destabilizing than that of the (relatively smaller) MOMOCH2
group–TMS in 35. Therefore, the metallocarbenoid reaction
occurs preferentially via the more stable 35 to give the tetracyclic
γ-lactam 32 as the major product. Reaction via the less preferred
reaction conformer 35′ results in the minor γ-lactam product 33.
Stability of the tetracyclic γ-lactams
As revealed by the results above, the propensity of the tetracyclic
γ-lactams to undergo ring opening at the cyclopropyl moiety
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Experimental section
General experimental details
Melting points are uncorrected. Infrared spectra were recorded
either as neat oil or as a film (CH2Cl2) on NaCl plates; only diag-
nostic signals were reported. NMR spectra were recorded at 200
or 300 MHz in deuteriochloroform (CDCl3) unless otherwise
noted. The chemical shifts were reported in parts per million (δ)
relative to the appropriate reference signal: residual chloroform
1
(δH 7.26) singlet for H NMR and the CDCl3 triplet centered at
δ 77.0 for 13C NMR. Multiplicities of 1H NMR signals were
given as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad, and coupling constants (J) are given in Hz. High-resol-
ution mass spectral analysis was obtained using either electron-
impact (70 ev) or chemical-ionization (NH3) mode. Reaction
progress was monitored by thin-layer chromatography on silica
gel 60F254 precoated (0.25 mm) on aluminum-backed sheets.
Flash chromatography was performed on silica gel 60 Å. Pet-
roleum ether (PE) is the fraction with bp 35–60 °C. Air and
moisture sensitive reactions were conducted under a static
pressure of Ar. PhMe, CH2Cl2 CH3CN, DMF and DBU were
dried by distillation from CaH2. MeOH and EtOH were dried by
distillation from magnesium metal in the presence of catalytic
amounts of iodine. THF and Et2O were dried by distillation from
sodium using sodium benzophenone ketyl as indicators. All
organic extracts were dried over anhydrous Na2SO4. All crude
reaction products were purified by flash column chromatography
unless noted otherwise.
Scheme 5 BF3·OEt2-mediated rearrangement of tetracyclic γ-lactams
19h, 39 and 40.
the idea that the N-BTMSM group could have sterically shielded
the BF3·OEt2 from effectively coordinating to the lactam carbo-
nyl oxygen. To determine if this was the case, the N-BTMSM
group in 19h was removed via oxidative deprotection (CAN) fol-
lowed by base hydrolysis (Na2CO3) to afford 39 in 51% yield
over two steps. Although exposure of 39 to 20 mol% BF3·OEt2
in DCE at rt did not lead to 41b, we found that upon heating the
reaction mixture under reflux for 48 h, 41b was formed in a
respectable yield of 70% (Scheme 5). Interestingly, the N-
butenyl compound 40, which was prepared from 39, behaved
similarly to 19h; that is, no rearrangement to 41c was observed
under the same conditions (BF3·OEt2, DCE, rt or 80 °C). These
results suggest that rearrangement is less likely if an N-substitu-
ent is present in the γ-lactam moiety of tetracyclic γ-lactams car-
rying an electron-withdrawing indole-N-PhSO2 (or N-MeSO2)
group.
General procedure for the metal-catalyzed reaction of diazo-
amides 10. The appropriate rhodium(II) catalyst (2 mol%) or
Cu(II) catalyst (4 mol%) was suspended/dissolved in dry CH2Cl2
under Ar. A solution of the diazo compound in dry CH2Cl2 was
added, via canula, under Ar to the catalyst suspension/solution
either at rt or 40 °C. After the reaction was complete, the solvent
was removed in vacuo, and the crude mixtures were purified.
Conclusion
Rh2(OAc)4-catalyzed reaction of α-diazoamides 10a,b. Di-
azoamides 10a,b were treated with Rh2(OAc)4 according to the
general procedure. It was found that the reaction of diazoamide
10a was complete at rt within 72 h. In the case of 10b, the reac-
tion was found to be much slower and there was a significant
amount of starting 10b after 3 h at rt as judged by TLC; the reac-
tion was brought to completion by heating the mixture at reflux
for 6 h.
The above studies on the metal-catalyzed reactions of the N-
BTMSM indolylmethyl diazoamides have shown that: (1) the
use of the N-BTMSM group is essential for enhancing site-selec-
tivity via its conformational control about the amide N–C(O)
unit wherein the metallocarbenoid reaction at the indole moiety
is promoted; (2) the N-BTMSM group also provided confor-
mational bias about the N–Cα sigma in N–Cα-branched diazo-
amides, which afforded excellent chemoselectivity in the
metallocarbenoid reaction; (3) the chemoselectivity of the reac-
tion was also influenced to some extent by the nature of the cata-
lyst employed, and especially in the N–Cα-branched
diazoamides where the use of a less electrophilic catalyst
[Rh2(cap)4] led to excellent chemoselectivity; (4) substitution at
the C(3) position of the indole ring had a noticeable steric effect
on the chemoselectivity of the reaction; and (5) the electronic
effects of the α-substituent at the diazo carbon and the indole N-
substituent governed whether the tetracyclic γ-lactams or tri-
cyclic indole derivatives were obtained as major or exclusive
products. In this study, our results indicate that cyclopropyl inter-
mediates (tetracyclic-γ-lactams) are formed enroute to the tri-
cyclic indole derivatives.
Methyl 2-ethyl-2,3,3b,8-tetrahydro-3-oxo-8-(phenylsulfonyl)-
pyrrolo[3′,4′ : 1,3]cycloprop[1,2-b]indol-3a(1H)-carboxylate (11).
Chromatography: 1 : 1 v/v PE–EtOAc; yield: 28%. Pale yellow
1
solid; IR (film) 1734, 1694 cm−1; H NMR (300 MHz) δ 1.18
(t, 3 H, J = 7.3 Hz), 3.09 (s, 3 H), 3.15 (s, 1 H), 3.35 (dq, 1 H, J
= 14.2, 7.3 Hz), 3.55 (dq, 1 H, J = 14.2, 7.3 Hz), 3.74 (d, 1 H, J
= 10.9 Hz), 4.82 (d, 1 H, J = 10.9 Hz), 7.06–7.14 (m, 1 H),
7.29–7.39 (m, 2 H), 7.45–7.54 (m, 2 H, 7.56–7.64 (m, 1 H),
7.71 (d, 1 H, J = 7.7 Hz), 7.85–7.94 (m, 2 H).
Methyl
1-[(1-phenylsulfonylindol-2-yl)methyl]-2-pyrrolidi-
none-3-carboxylate (12). Chromatography: 1 : 1 v/v PE–EtOAc;
1
yield: 31%. Colorless oil; IR (film) 1741, 1696 cm−1; H NMR
(300 MHz) δ 2.25–2.40 (m, 1 H), 2.41–2.54 (m, 1 H), 3.45
Org. Biomol. Chem., 2012, 10, 4597–4608 | 4605
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1
(ddd, 1 H, J = 8.2, 8.2, 5.8 Hz), 3.53 (dd, 1 H, J = 9.2, 7.3 Hz),
3.66 (ddd, 1 H, J = 8.2, 8.2, 5.8 Hz), 3.81 (s, 3 H), 4.88 (d, 1 H,
J = 16.2 Hz), 4.98 (d, 1 H, J = 16.2 Hz), 6.53 (s, 1 H),
7.18–7.34 (m, 2 H), 7.38–7.46 (m, 3 H), 7.48–7.57 (m, 1 H),
7.74–7.83 (m, 2 H), 8.12 (d, 1 H, J = 8.6 Hz); 13C NMR
(75 MHz) δ 22.5, 41.5, 46.0, 48.0, 52.9, 110.6, 114.6, 114.7,
120.9, 124.0, 124.8, 126.2, 129.3, 134.0, 135.3, 137.2, 138.2,
170.0, 170.8; HRMS (EI) calcd for C21H20N2O5S (M+)
412.1093, found 412.1095.
3453, 1756, 1734 cm−1; H NMR (300 MHz) δ 0.17 (s, 9 H),
0.18 (s, 9 H), 2.12 (s, 1 H), 3.77 (s, 3 H), 4.12 (d, 1 H, J = 2.5
Hz), 4.99 (d, 1 H, J = 2.5 Hz), 6.61 (br d, 1 H, J = 2.5 Hz), 7.14
(ddd, 1 H, J = 8.1, 7.4, 0.9 Hz), 7.20–7.28 (m, 1 H), 7.35–7.42
(m, 1 H), 7.61 (d, 1 H, J = 8.1 Hz), 8.30–8.38 (br s, 1 H); 13C
NMR (75 MHz) δ −0.1, 0.1, 38.9, 52.6, 54.5, 60.5, 104.5,
111.2, 120.5, 120.7, 123.1, 127.8, 132.4, 136.6, 161.5, 167.6;
HRMS (EI) calcd for C20H30N2O3Si2 (M+) 402.1795, found
402.1809.
cis-Methyl 1-[(1-phenylsulfonylindol-2-yl)methyl]-4-methyl-2-
azetidinone-3-carboxylate (cis-13). Chromatography: 1 : 1 v/v
Methyl 2-[bis(trimethylsilyl)methyl]-1,2,3,4-tetrahydro-3-oxo-
pyrazino[1,2-a]indole-4-carboxylate (17). Chromatography: 7 : 1
v/v PE–EtOAc; yield: 8%. White foam; IR (film) 1734,
PE–EtOAc; yield: 4%. Colorless oil; IR (film) 1768, 1734 cm−1
;
1H NMR (300 MHz) δ 1.29 (d, 3 H, J = 5.9 Hz), 3.76 (s, 3 H),
4.03–4.08 (m, 2 H), 4.68 (d, 1 H, J = 17.2 Hz), 4.85 (d, 1 H, J =
17.2 Hz), 6.65 (s, 1H), 7.20–7.30 (m, 2 H), 7.35–7.55 (m, 4 H),
7.69–7.71(m, 2 H), 8.10 (d, 1 H, J = 8.4 Hz); HRMS (EI) calcd
for C21H20N2O5S (M+) 412.1093, found 412.1089.
1
1655 cm−1; H NMR (CD3CN, 300 MHz) δ −0.05–0.25 (br s,
18 H), 3.71 (s, 3 H), 3.92–4.10 (br s, 1 H), 4.59 (d, 1 H, J =
16.5 Hz), 4.90 (br d, 1 H, J = 16.5 Hz), 5.60–5.81 (br s, 1 H),
6.31–6.57 (br s, 1 H), 7.12 (ddd, 1 H, J = 7.7, 7.7, 1.3 Hz), 7.17
(ddd, 1 H, J = 7.7, 7.7, 1.3 Hz), 7.27–7.42 (br s, 1 H), 7.58 (br
d, 1 H, J = 7.7 Hz); HRMS (EI) calcd for C20H30N2O3Si2 (M+)
402.1795, found 402.1800.
trans-Methyl 1-[(1-phenylsulfonylindol-2-yl)methyl]-4-methyl-
2-azetidinone-3-carboxylate (trans-13). Chromatography: 1 : 1
v/v PE–EtOAc; yield: 10%. Colorless oil; IR (film) 1769,
1
1734 cm−1; H NMR (300 MHz) δ 1.35 (d, 3 H, J = 6.3 Hz),
Rh2(OAc)4-catalyzed reaction of α-diazoamides 23a,c,e. Com-
pounds 23a,c,e were treated with Rh2(OAc)4 at rt following the
procedure described for the reaction of α-diazoamides 10. For
23a, the reaction was complete only after 24 h, but for 23c,e
complete reaction occurred within 10 min.
3.66 (d, 1 H, J = 2.2 Hz), 3.77 (s, 3 H), 4.10–4.15 (m, 1 H),
4.65 (d, 1 H, J = 17.8 Hz), 4.90 (d, 1 H, J = 17.8 Hz), 6.74 (s, 1
H), 7.20–7.30 (m, 2 H), 7.35–7.55 (m, 4 H), 7.69–7.71 (m, 2
H), 8.10 (d, 1 H, J = 8.4 Hz); 13C NMR (75 MHz) δ 17.6, 38.8,
51.9, 52.9, 61.4, 111.5, 114.8, 121.3, 124.2, 125.1, 126.5, 129.7,
134.0, 135.0, 138.8, 164.8, 167.8; HRMS (EI) calcd for
C21H20N2O5S (M+) 412.1093, found 412.1089.
Ethyl 2-[bis(trimethylsilyl)methyl]-2,3,3b,8-tetrahydro-3b-methyl-
3-oxo-8-(phenylsulfonyl)-pyrrolo[3′,4′ : 1,3]cycloprop[1,2-b]indol-
3a(1H)-carboxylate (24a). Chromatography: 2 : 1 PE–Et2O;
1
yield: 54%. Colorless oil; IR (film) 1679, 1730 cm−1; H NMR
4-Carbomethoxy-2-ethyl-9-phenylsulfonyl-4,9-dihydro-1H-
pyrido[3,4-b]indol-3(2H)-one (14). Compound 14 was formed
upon standing a solution of 11 (8 mg) in CDCl3 overnight. After
purification using PE–EtOAc (1 : 1) as the eluent, a pale yellow
powder (8 mg, 100%) was obtained, mp 177–180 °C; IR (film)
(CD3CN, 300 MHz) δ 0.17 (s, 18 H), 0.78 (t, 3 H, J = 7.2 Hz),
1.46 (s, 3 H), 2.82–2.94 (br s, 1 H), 3.56–3.68 (m, 2 H), 3.69 (d,
1 H, J = 12.1 Hz), 4.81 (d, 1 H, J = 12.1 Hz), 7.15 (br t, 1 H, J
= 7.8 Hz), 7.21–7.30 (m, 1 H), 7.46 (br d, 2 H, J = 8.0 Hz), 7.46
(br t, 2 H, J = 7.8 Hz), 7.65–7.73 (m, 1 H), 7.83–7.92 (m, 2 H);
13C NMR (CD3CN, 75 MHz) δ 0.0, 11.2, 13.1, 38.6, 39.1, 39.2,
48.1, 60.0, 60.9, 114.9, 124.5, 125.7, 127.2, 128.1, 129.9, 132.8,
134.2, 139.8, 141.9, 163.8, 165.9; HRMS (EI) calcd for
C28H38N2O5SSi2 (M+) 570.2040, found 570.2031.
1
1744, 1653 cm−1; H NMR (300 MHz) δ 1.29 (t, 3 H, J = 6.5
Hz), 3.70 (s, 3 H), 3.60–3.78 (m, 2 H), 4.68 (t, 1 H, J = 4.0 Hz),
4.88 (d, 1 H, J = 18.6, 4.0 Hz), 4.98 (d, 1 H, J = 18.6, 4.0 Hz),
7.29 (dd, 1 H, J = 8.2, 1.3 Hz), 7.36 (ddd, 1 H, J = 8.6, 8.2, 1.3
Hz), 7.45–7.52 (m, 3 H), 7.52–7.60 (m, 1 H), 7.75–7.82 (m, 2
H), 8.06–8.11 (m, 1 H); 13C NMR (75 MHz) δ 12.1, 43.5, 46.5,
48.0, 53.1, 113.9, 114.8, 119.2, 125.0, 126.0, 127.1, 127.8,
129.0, 130.0, 134.6, 136.8, 138.2, 163.0, 169.0; HRMS (EI)
calcd for C21H20N2O5S (M+) 412.1093, found 412.1089.
2-[Bis(trimethylsilyl)methyl]-2,3,3b,8-tetrahydro-3b-methyl-3-
oxo-8-(phenylsulfonyl)-pyrrolo[3′,4′ : 1,3]cycloprop[1,2-b]indol-
3a(1H)-one (24c) and 1-[bis(trimethylsilyl)methyl]-4-(phenylsul-
fonyl-3-methyl-indol-2-yl)-2-azetidinone (25c). Chromatography:
2 : 1 v/v PE–Et2O. Compounds 24c and 25c were obtained as an
inseparable 3 : 1 mixture in 72% combined yield. The ratio of
24c : 25c was based on the integration of the doublet due to the
H-1′ at δ 4.81 in the tetracyclic γ-lactam 24c and the double
doublet due to the H-3 at δ 3.01 in the β-lactam 25c. IR (film)
2-[Bis(trimethylsilyl)methyl]-4-carbomethoxy-4,9-dihydro-1H-
pyrido[3,4-b]indol-3(2H)-one (15). Chromatography: 7 : 1 v/v
PE–EtOAc; yield: 65%. Pale yellow solid, mp 209–210 °C; IR
(film) 3456, 1740, 1614 cm−1; 1H NMR (300 MHz) δ 0.05–0.15
(br s, 9 H), 0.15–0.25 (br s, 9 H), 1.75–1.90 (br s, 1 H), 3.68 (s,
3 H), 4.45–4.57 (m, 1 H), 4.73–4.90 (m, 2 H), 7.11–7.17 (m, 1
H), 7.22 (ddd, 1 H, J = 6.9, 6.9, 1.5 Hz), 7.32–7.37 (m, 1 H),
7.58 (d, 1 H, J = 7.7 Hz), 8.06–8.15 (br s, 1 H); 13C NMR
(75 MHz) δ 0.0, 48.1, 49.0, 51.2, 52.5, 106.0, 111.1, 119.0,
120.8, 123.1, 125.5, 127.9, 137.2, 163.8, 170.2; HRMS (EI)
calcd for C20H30N2O3Si2 (M+) 402.1795, found 402.1786.
1668, 1737 cm−1
;
Tetracyclic γ-lactam 24c: 1H NMR
(300 MHz) δ 0.27 (s, 9 H), 0.30 (s, 9 H), 0.85 (d, 1 H, J = 1.9
Hz), 1.41 (s, 3 H), 2.85–2.95 (br s, 1 H), 3.65 (dd, 1 H, J = 11.1,
1.9 Hz), 4.81 (d, 1 H, J = 11.1 Hz), 7.10 (ddd, 1 H, J = 8.0, 8.0,
0.6 Hz), 7.68–7.72 (m, 2 H), 7.84 (d, 1 H, J = 11.4 Hz),
7.19–7.62 (m, 5 H, extensive overlap of signals for indole and
SO2Ph hydrogens); 13C NMR (75 MHz) δ 0.6, 0.9, 11.0, 26.9,
34.7, 38.1, 49.8, 53.8, 116.9, 124.1, 124.9, 127.8, 128.1, 129.2,
134.0, 135.0, 135.9, 142.2, 168.2.
Methyl 1-[bis(trimethylsilyl)methyl]-4-(1H-indol-2-yl)-2-azeti-
dinone-3-carboxylate (16). Chromatography: 7 : 1 v/v PE–
EtOAc; yield: 17%. White solid, mp 167–169 °C; IR (film)
4606 | Org. Biomol. Chem., 2012, 10, 4597–4608
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1
(c) G. Bartoli, G. Bencivenni and R. Dalpozzo, Chem. Soc. Rev., 2010,
39, 4449.
3 Pd-catalyzed reaction: (a) S. Cacchi and G. Fabrizi, Chem. Rev., 2005,
105, 2873; (b) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111, PR215;
(c) Ir-catalyzed reaction: D. W. Robbins, T. A. Boebel and J. F. Hartwig,
J. Am. Chem. Soc., 2010, 132, 4068.
β-lactam 25c: H NMR (300 MHz) δ 0.10 (s, 9 H), 0.20 (s, 9
H), 2.13 (s, 1 H), 2.30 (s, 3 H), 3.01 (dd, 1 H, J = 13.9, 2.8 Hz),
3.27 (dd, 1 H, J = 13.9, 5.6 Hz), 5.61 (dd, 1 H, J = 5.6, 2.8 Hz),
8.21 (d, 1 H, J = 11.4 Hz), 7.19–7.62 (m, 8 H, extensive overlap
of signals for indole and SO2Ph hydrogens); 13C NMR
(75 MHz) δ 0.3, 10.0, 30.3, 39.8, 43.4, 115.9, 116.8, 118.8,
124.1, 125.7, 126.1, 127.8, 129.1, 131.7, 132.1, 133.8, 137.3,
167.1.
4 S. Patil and R. Patil, Curr. Org. Synth., 2007, 4, 201.
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(c) T. Sawada, D. E. Fuerst and J. L. Wood, Tetrahedron Lett., 2003, 44,
4919.
2-[Bis(trimethylsilyl)methyl]-1,2,3b,8-tetrahydro-3-oxo-3,8-
dimethylpyrrolo[3′,4′ : 1,3]cycloprop[1,2-b]indol-3(3aH)-one (24e).
Chromatography: 10 : 1 v/v PE–EtOAc; yield: 73%. White solid,
mp 148–150 °C; IR (film) 1664 cm−1; H NMR (300 MHz) δ
1
7 (a) S. Muthusamy and P. Srinivasan, Tetrahedron Lett., 2005, 46, 1063;
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8 W. W. Chan, S.-H. Yeung, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org.
Lett., 2010, 12, 604.
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4277; (b) E. Wenkert, M. E. Alonso, H. E. Gottlieb and L. E. Sanchez, J.
Org. Chem., 1977, 42, 3945; (c) W. J. Welstead Jr., H. F. Stauffer Jr. and
L. F. Sancilio, J. Med. Chem., 1974, 17, 544; (d) R. W. Jackson and R.
H. Manske, Can. J. Res., 1935, 13B, 170.
0.16 (s, 9 H), 0.18 (s, 9 H), 1.21 (d, 1 H, J = 1.8 Hz), 1.54 (s, 3
H), 2.86 (s, 3 H), 3.08–3.18 (br s, 1 H), 3.55(dd, 1 H, J = 11.3,
1.8 Hz), 3.80 (d, 1 H, J = 11.3 Hz), 6.70 (br d, 1 H, J = 7.5 Hz),
6.86 (ddd, 1 H, J = 7.5, 7.5, 0.9 Hz), 7.16 (ddd, 1 H, J = 7.5,
7.5, 0.9 Hz), 7.28 (d, 1 H, J = 7.5 Hz); 13C NMR (75 MHz) δ
1.2, 10.8, 24.0, 34.1, 33.8, 37.2, 47.8, 56.2, 111.0, 120.2, 124.0,
128.0, 134.2, 149.5, 169.2; HRMS (EI) calcd for C20H32N2OSi2
(M+) 372.2053, found 372.2054.
10 S. J. Hedley, D. L. Ventura, P. M. Dominiak, C. L. Nygren and
H. M. L. Davies, J. Org. Chem., 2006, 71, 5349.
Ethyl
1-[bis(trimethylsilyl)methyl]-4-(1-phenylsulfonyl-3-
11 (a) M. Salim and A. Capretta, Tetrahedron, 2000, 56, 8063;
(b) E. Cuevas-Yañez, J. M. Muchowski and R. Cruz-Almanza, Tetrahe-
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2001, 42, 6835; (d) J. Yang, H. Wu, L. Shen and Y. Qin, J. Am. Chem.
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Angew. Chem., Int. Ed., 2008, 47, 3618.
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I. C. Richards, Tetrahedron, 1998, 54, 9689; (b) F. Zaragoza, Tetrahe-
dron, 1995, 51, 8829; (c) M. P. Doyle, M. S. Shanklin, S. M. Oon, H.
Q. Pho, F. R. van de Heide and W. R. Veal, J. Org. Chem., 1988, 53,
3384.
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S. Ikegami, Synlett, 1994, 1031; (b) N-(Neopentyl): M. P. Doyle, R.
J. Pieters, J. Taunton, H. Q. Pho, A. Padwa, D. L. Hertzog and
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A. G. H. Wee, B. S. Liu and L. Zhang, J. Org. Chem., 1992, 57, 4404;
(d) N-(2,4,6-Trimethylbenzyl): C. H. Yoon, A. Nagle, C. Chen,
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Z. Chen, Z. Chen, Y. Jiang and W. Hu, Synlett, 2004, 1763.
14 (a) N-(4-Nitrophenyl): M. Anada and S.-H. Hashimoto, Tetrahedron
Lett., 1998, 39, 79; (b) N-(Carbalkoxyethyl): C. H. Yoon, M.
J. Zaworotko, B. Moulton and K. W. Jung, Org. Lett., 2001, 3, 3539;
(c) N-(benzylchromium tricarbonyl): C. A. Merlic, A. L. Zechman and
M. M. Miller, J. Am. Chem. Soc., 2001, 123, 11101.
methyl-indol-2-yl)-2-azetidinone-3-carboxylate (25a). Chromato-
graphy: 2 : 1 v/v PE–Et2O; yield: 13%. Compound 25a was
obtained as an inseparable 1 : 3 mixture of cis- and trans-diaster-
eomers; the cis : trans ratio was determined based on the inte-
gration of the H-4 signal of the β-lactam. IR (film) 1731,
1
1750 cm−1; H NMR (300 MHz, discernible signals for cis-dia-
stereomer in square brackets) δ 0.10 (s, 9 H), 0.21 and [0.22] (s,
9 H), [1.06] and 1.33 (t, 3 H, J = 7.3 Hz), [2.12] and 2.18 (s, 1
H), 2.32 and [2.41] (s, 3 H), 4.20 (d, J = 2.5 Hz) and [4.42 (d, J
= 5.7 Hz)] (1 H), [3.92–4.02 (m)] and 4.22–4.36 (m) (2 H),
[5.90 (d, J = 5.7 Hz)] and 5.94 (d, J = 2.5 Hz) (1 H), 7.27–7.54
(m, extensive overlap of signals for indole and SO2Ph hydro-
gens), 7.67–7.75 (m, extensive overlap of signals for indole and
SO2Ph hydrogens), [7.98 (dd, J = 7.7, 1.5 Hz)] and 8.22 (d, J =
8.5 Hz) (1 H); 13C NMR (75 MHz, discernible signals for cis-
diastereomer in square brackets) δ 0.4 and [0.6], 0.8 and [1.4],
10.6 and [10.7], [14.1] and 14.5, [39.5] and 39.9, 53.1 and
[54.5], [59.4] and 60.3, [61.5] and 62.1, [115.1] and 116.1,
119.2 and [119.4], 122.7 and [122.9], [123.9] and 124.3, [125.7]
and 126.2, 126.8 and [127.0], [129.2] and 129.3, 130.5 and
[131.5], 131.7 and, [133.9] and 134.1, [137.2] and 137.4, 138.2
and [139.1], 162.3 and [163.2], 167.4; HRMS (EI) calcd for
C28H38N2O5SSi2 (M+) 570.2040, found 570.2029.
15 (a) M. P. Doyle, M. N. Protopopova, W. R. Winchester and K. L. Daniel,
Tetrahedron Lett., 1992, 33, 7819; (b) J. Clayden and K. Tchabanenko,
Chem. Commun., 2000, 317.
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(b) A. G. H. Wee, S. C. Duncan and G.-J. Fan, Tetrahedron: Asymmetry,
2006, 17, 297; (c) A. G. H. Wee and S. C. Duncan, J. Org. Chem., 2005,
70, 8372.
18 Preliminary report: B. Zhang and A. G. H. Wee, Chem. Commun., 2008,
4837.
Acknowledgements
19 (a) R. B. Kolhatkar, S. K. Ghorai, C. George, M. A. E. Reith and A.
K. Dutta, J. Med. Chem., 2003, 46, 2205; (b) R. Silvestri, G. De Martino,
G. La Regina, M. Artico, S. Massa, L. Vargiu, M. Mura, A. G. Loi,
T. Marceddu and P. La Colla, J. Med. Chem., 2003, 46, 2482; (c) C.-
L. Lidwine, J. Benoit and M. Jean-Yves, Synlett, 2001, 848;
(d) C. Bhattacharya, P. Bonfante, A. Deagostino, Y. Kapulnik, P. Larini,
E. G. Occhiato, C. Prandi and P. Venturello, Org. Biomol. Chem., 2009,
7, 3413.
We thank the Natural Sciences and Engineering Research
Council, Canada and the University of Regina for financial
support of our research program.
Notes and references
1 (a) T. C. Barden, Top. Heterocycl. Chem., 2010, 26, 31; (b) Y.-J. Wu,
Top. Heterocycl. Chem., 2010, 26, 1; (c) W. Gul and M. Hamann, Life
Sci., 2005, 78, 42.
20 (a) M. G. Saulnier and G. W. Gribble, J. Org. Chem., 1982, 47, 757;
(b) D. L. Comins and M. O. Killpack, J. Org. Chem., 1987, 52, 104;
(c) Commercially available.
2 (a) R. J. Sundberg, Top. Heterocycl. Chem., 2010, 26, 47; (b) M. Bandini
and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608;
21 R. F. Borch, M. D. Bernstein and H. D. Durst, J. Am. Chem. Soc., 1971,
93, 2897.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4597–4608 | 4607

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22 J. P. Marino Jr., M. H. Osterhout, A. T. Price, S. M. Sheehan and
A. Padwa, Tetrahedron Lett., 1994, 35, 849.
23 D. F. Taber, R. E. Ruckle Jr. and M. J. Hennesy, J. Org. Chem., 1986, 51,
4077.
27 (a) E. Wenkert, P. D. R. Moeller and S. R. Piettre, J. Am. Chem. Soc.,
1988, 110, 7188; (b) D. Nagarathnam, M. Vedachalam and P.
C. Srinivasan, Synthesis, 1983, 156.
28 M. Kizil, B. Patro, O. Callaghan, J. A. Murphy, M. B. Hursthouse and
D. Hibbs, J. Org. Chem., 1999, 64, 7856.
29 (a) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873 and references
cited therein (b) A. G. H. Wee and B. Zhang, Tetrahedron Lett., 2007, 48,
4135.
24 (a) We also examined the Rh2(OAc)4-catalyzed reaction of the α-acetyl
substituted (10, R = PhSO2, R1 = Et, R2 = Ac) and α-unsubstituted
(10, R = PhSO2, R1 = Et, R2 = H) diazoamides. The reaction of the
α-acetyl substituted diazoamide gave a complex product mixture and no
starting material was recovered. With the α-unsubstituted diazoamide,
a low yield (18%) of the cyclopropanation product was obtained;
the expected γ- and β-lactams, which could arise from C–H insertion
at the N-ethyl moiety, were not detected (b) Assignment of stereo-
chemistry was based on the JH-3,H-4: Jcis = ∼5.7 Hz, Jtrans = ∼2.4 Hz; see
ref. 13c.
30 Crystal data for 34: C20H32N2O4SSi2, Mr = 452.72, monoclinic, space
group P21/n, a = 9.0478(9), b = 18.6125(18), c = 14.1521(14) Å, β =
96.3590(10)o, V = 2368.6(4) Å3, T = 193(2) K, Z = 4, Dcalc = 1.270 Mg
m
−3, F(000) = 968, μ = 0.265 mm−1. 15 535 reflections were measured
on a Nonius Kappa CCD diffractometer, 5381 were independent (I >
2σ(I)). Final R1 = 0.0410, wR2 = 0.1103.
25 (a) M. P. Doyle, A. B. Dyatkin and C. L. Autry, J. Chem. Soc., Perkin
Trans. 1, 1995, 619; (b) J. S. Clark, A. G. Dossetter, Y.-S. Wong, R.
J. Townsend, W. G. Whittingham and C. A. Russell, J. Org. Chem.,
2004, 69, 3886.
31 Three relatively stable tetracylic γ-lactams 11, 19g, and 24e, which were
obtained from the metal-catalyzed reaction of N–Cα-unbranched indolyl
diazoamides, rearranged to tricyclic products, 14, 18g, and 27, when
stored as CDCl3 solutions. These outcomes were attributed to catalysis by
trace amounts of HCl.
26 For compound characterization, see ESI†.
4608 | Org. Biomol. Chem., 2012, 10, 4597–4608
This journal is © The Royal Society of Chemistry 2012