Demonstration of 14-20-membered intramolecular carbonyl ylides: Diastereoselective synthesis of macrocycles incorporating spiro-indolooxiranes

Article abstract of DOI:10.1016/j.tetlet.2011.02.052

A range of macrocycles (13-19-membered) possessing spiro-indolooxirane unit were synthesized with complete diastereoselectivity in good yield by the rhodium(II) acetate catalyzed reaction of substituted cyclic diazoamides in dry dichloromethane. The reaction proceeds via the formation of the corresponding macrocyclic carbonyl ylide followed by a con-rotatory electrocyclization process.

Full text of DOI:10.1016/j.tetlet.2011.02.052

Tetrahedron Letters 52 (2011) 1934–1937
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Tetrahedron Letters
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Demonstration of 14–20-membered intramolecular carbonyl ylides:
diastereoselective synthesis of macrocycles incorporating spiro-indolooxiranes
⇑
Sengodagounder Muthusamy , Thangaraju Karikalan, Eringathodi Suresh
School of Chemistry, Bharathidasan University, Tiruchirappalli 620 024, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of macrocycles (13–19-membered) possessing spiro-indolooxirane unit were synthesized with
complete diastereoselectivity in good yield by the rhodium(II) acetate catalyzed reaction of substituted
cyclic diazoamides in dry dichloromethane. The reaction proceeds via the formation of the corresponding
macrocyclic carbonyl ylide followed by a con-rotatory electrocyclization process.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 December 2010
Revised 9 February 2011
Accepted 11 February 2011
Available online 17 February 2011
Keywords:
Carbonyl ylide
Diazoamide
Macrocycle
Rhodium acetate
Spiro-indolooxirane
The reaction of diazocarbonyl compounds with rhodium(II)
carboxylate is a well illustrated method to produce rhodium carb-
enoids, which experience an array of reactions, such as cycloprop-
anation, C–H or heteroatom-H insertion, and ylide formation.1 The
metal-carbenoid generated transient ylides can undergo 1,3-dipo-
lar cycloaddition reaction with a range of dipolarophiles,2 rear-
rangement reactions,2c or cyclization to three-membered ring
(aziridine or epoxide formation). However, the 1,3-dipolar cycload-
dition reactions of carbonyl ylides are well-known rather than
their electrocyclization. Three-membered heterocyclic rings pro-
vide an uncommon combination of reactivity, synthetic flexibility,
and atom economy.3 An oxirane was formed4 in only 7% yield,
when the reaction of dimethyl diazomalonate with benzaldehyde
was performed at 125 °C in the presence of 1 mol % of Cu(acac)2,
but there was no formation of oxirane when the reaction was cat-
alyzed by Rh2(OAc)4. The metal-catalyzed decomposition of ethyl
diazoacetate in the presence of aldehydes does not effectively pro-
duce oxiranes.5 Instead, dioxolanes are formed, whereby, the inter-
mediate ylide undergoes a 1,3-diploar cycloaddition with a second
equivalent of aldehyde. Diazocarbonyl compounds were not found
to produce the oxirane ring system via intermolecular carbonyl
ylides until Doyle6 and Davies7 groups reported stereospecific
epoxide formation from rhodium acetate catalyzed diazo decom-
position of aryldiazoacetate with aryl aldehydes or ketones. We
have also reported8 the stereoselective process to synthesize
spiro-indolooxiranes from cyclic diazoamides in an intermolecular
manner.
The intramolecular carbonyl ylide 2, derived from diazo ketone
1, in the presence of Rh(II)-catalyst afforded9 oxirane 3 as a tran-
sient intermediate to furnish dihydropyridone 4 (Scheme 1). The
fused oxirane ring system was an isolated example reported during
the synthesis of komaroviquinone10 skeleton via intramolecular
carbonyl ylide. To the best of our knowledge, only five to seven-
membered2b and a lonely example11 for 10-membered intramolec-
ular carbonyl ylides are available in the literature. Many naturally
existing macrocycles possessing oxirane unit were known to have
biological activity, for example, laulimalide,12 radicicol,13 may-
tansinoid,14 macrocyclic trichothecenes.15 In continuation of our
O
O
Ph
R
Rh(II)
O
N2
Ph
N
R
N
O
O
1
2
OH
O
N
Ph
R
O
Ph
N
R
4
3
⇑
Corresponding author. Tel.: +91 431 2407053; fax: +91 431 2407045.
E-mail address: muthu@bdu.ac.in (S. Muthusamy).
Scheme 1. Synthesis of dihydropyridone 4.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.052

S. Muthusamy et al. / Tetrahedron Letters 52 (2011) 1934–1937
1935
Table 1
CHO
Synthesis of macrocyclic spiro-oxiranes 10
K2CO3 / DMF
Br
+
( )n
Br
R1
Entry Aldehyde 5
n
R2 Yield of Yield of
OH
rt, 10-12 hr
9a (%)
10a (%)
5
6
1
2
3
4
5
6
7
8
9
2-Hydroxybenzaldehyde
2
4
5
6
8
6
6
6
4
6
H
H
H
H
H
H
H
90 (9a)
60 (10a)
R1 = OCH3, NO2
2-Hydroxybenzaldehyde
2-Hydroxybenzaldehyde
2-Hydroxybenzaldehyde
2-Hydroxybenzaldehyde
2-Hydroxy-4-methoxy benzaldehyde
2-Hydroxy-3-nitro benzaldehyde
2-Hydroxybenzaldehyde
3-Hydroxybenzaldehyde
3-Hydroxybenzaldehyde
86 (9b) 63 (10b)
88 (9c) 67 (10c)
85 (9d) 70 (10d)
81 (9e)
89 (9f)
82 (9g)
n = 2,4,5,6,8
Br
( )n
CHO
N2
59 (10e)
71 (10f)
67 (10g)
R2
K2CO3 / DMF
rt, 8-9 hr
R1
+
O
O
Cl 83 (9h) 68 (10h)
H
H
N
H
84 (9i)
82 (9j)
62 (10i)
69 (10j)
8a; R2 = H
8b; R2 = Cl
7
10
a
Yields are unoptimized and refer to isolated yields.
R2
R2
R2
R2
N
N
N2
Rh2(OAc)4
( )n
O
O
O
Dry DCM,rt
15-25min
N
( )n
O
N
N2
H
Rh2(OAc)4
CHO
CHO
R1
Rh2(OAc)4
O
( )n
( )n
n = 2,4,5,6,8
O
O
dry DCM
CHO
R1
O
O
9
10
R1
R1
Scheme 2. Synthesis of macrocyclic spiro-oxiranes.
9
11
R2
R2
N
N
thermal
( )n
( )n
O
O
O
O
con-
rotatory
H
H
O
O
R1
R1
10
12
Scheme 3. Plausible mechanism.
the substituted cyclic diazoamide 9a18 in the presence of
1.3 mol % of rhodium(II) acetate under argon atmosphere afforded
the 14-membered intramolecular macrocyclic carbonyl ylide and
its subsequent electrocyclization producing macrocycle 10a19 in
60% yield as a single isomer (Scheme 2, Table 1) based on the crude
NMR spectrum. The 1H NMR spectrum of 10a revealed the pres-
ence of one singlet at d = 4.51 ppm for OCH proton. Furthermore,
13C and DEPT-135 experiments disclosed the presence of charac-
teristic quaternary carbon at d = 61.31 ppm and a CH signal at
64.04 ppm, which unequivocally confirms the formation of the
spiro-oxirane ring unit. All other signals in 13C spectrum are due
to six CH2 carbons and eight CH carbons present with the assigned
structure. Next, the reaction of cyclic diazoamides 9b–e were car-
ried out under similar reaction conditions to generate the corre-
sponding 16–18 and 20-membered macrocyclic carbonyl ylides
and their subsequent electrocyclic ring closure afforded the
corresponding macrocycles 10b–e in good yield as a single isomer
(Table 2). The yield of the macrocyclic compounds 10b–e is compa-
rable with 10a even though there is an increase in size of the
macrocyclic core. The structure and stereochemistry of the repre-
sentative macrocycle 10d were confirmed based on the single
crystal X-ray analysis (Fig. 1).
Figure 1. ORTEP view macrocycle 10d.
interest in developing new synthetic strategies16 utilizing carbonyl
ylides, we herein demonstrate rhodium(II) acetate catalyzed
generation of 14–20-membered intramolecular carbonyl ylides
and their electrocyclization to afford the macrocycles incorpo-
rating spiro-indolooxiranes in good yield with complete
diastereoselectivity.
In order to demonstrate the macrocyclic carbonyl ylides, the
required substituted cyclic diazoamides 9a–j were assembled by
O-alkylation of hydroxybenzaldehydes 5 using dibromoalkanes 6
in the presence of potassium carbonate/DMF to afford17 the corre-
sponding bromobenzaldehydes 7 in 80–85% yield. Subsequent
N-alkylation of 3-diazooxiindoles 8a,b using bromobenzaldehydes
7 in the presence of potassium carbonate/DMF afforded the substi-
tuted diazoamides 9a–j in very good yield (Scheme 2).
The reaction of cyclic diazoamides having electron-donating or
electron-withdrawing substituent was planned. The reactions of
cyclic diazoamides having substituents on both benzaldehyde
Our aim is to demonstrate macrocyclic carbonyl ylides from
diazoamides 9 in the presence of a metal catalyst. Toward this,

1936
S. Muthusamy et al. / Tetrahedron Letters 52 (2011) 1934–1937
Table 2
lic diazoamides 9 yielded the corresponding macrocycles 10 in
good yield. However, para-substituted aromatic aldehydes teth-
ered on cyclic diazoamides 9 did not yield the product.
Synthesis of macrocyclic spiro-oxiranes 10
Entry
Macrocycles 10
Size of the
carbonyl
ylide 12
Size of the
macrocycles 10
We have studied the synthesis of macrocycles based on the
spacer length, and it plays an important role to form intramolecular
carbonyl ylides. It was found that the 14-membered intramolecular
carbonyl ylide is not favorable to produce the corresponding macro-
cycles, whereas the 13-membered or lesser did not afford the
product.
Mechanistically, we propose that the electron-deficient carbe-
noid carbon of rhodium(II) carbenoids 11 reacts with the remotely
placed oxygen atom of the aromatic aldehyde functionality afford-
ing the interesting 14 and 16–20-membered intramolecular car-
bonyl ylides 12 (Scheme 3). Then, the reaction is assumed to
proceed with stereospecific thermal con-rotatory electrocycliza-
tion of 12 to yield the observed macrocyclic epoxide 10 as a single
diastereoisomer. Interestingly, the formation of the carbonyl ylides
proceeds in an intramolecular manner and no products were ob-
served8 due to an intermolecular pathway.
O
H
O
1
2
3
N
O
14
16
17
13
15
16
10a
O
H
O
N
O
10b
10c
O
H
O
N
O
In conclusion, we have demonstrated for the first time the gen-
eration of 14–20-membered intramolecular carbonyl ylides from
cyclic diazoamides in the presence of rhodium(II) acetate as cata-
lyst. The subsequent electrocyclization of macrocyclic carbonyl
ylides furnished the 13–19-membered macrocycles incorporating
spiro-indolooxirane units with complete diastereoselectivity.
O
H
O
N
O
4
5
18
20
17
19
10d
O
H
Acknowledgments
O
N
O
This research was supported by the Council of Scientific and
Industrial Research (CSIR), New Delhi. We thank DST, New Delhi
for providing 400 MHz NMR facility under FIST program.
10e
Supplementary data
O
H
OCH3
O
Supplementary data (experimental procedures, characteriza-
tion data, proton and carbon spectra of all new compounds and
X-ray crystallographic data (CCDC-799942) for 10d) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.02.052.
N
O
6
7
8
9
18
18
18
17
17
17
17
16
10f
O
H
NO2
O
N
O
References and notes
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O
Cl
H
O
N
O
O
10h
H
O
N
O
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O
H
O
N
10
O
19
18
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10j
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9f,g and oxindole part 9h were performed under similar reaction
conditions to furnish macrocycles 10f–h in good yield. The reaction
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40.43 (CH2), 68.23 (CH2), 108.81 (@CH), 112.50 (@CH), 116.68 (quat-C), 118.40
(@CH), 120.41 (@CH), 121.88 (@CH), 124.75 (quat-C), 125.40 (@CH), 128.03
(@CH), 133.71 (quat-C), 135.91 (quat-C), 161.39 (quat-C), 166.66 (quat-C),
189.58 (CHO); HRMS (ESI) calcd for C21H21N3NaO3 [M+Na]+ 386.1519; found,
386.1509.
19. Macrocycle 10a: a solution of aldehyde substituted diazoamide 9a (100 mg,
1.0 mmol) and rhodium(II) acetate (1.6 mg, 1.3 mol %) in dichloromethane
(15 mL) was stirred at room temperature for 25 min. The reaction mixture was
concentrated under reduced pressure and purified on silica (hexane/EtOAc,
65:35) to afford 10a in 60% yield. Colorless solid; mp 150–152 °C; IR (neat):
17. Zhou, Y.; Zhao, Y.; O0Boyle, K. M.; Murphy, P. V. Bioorg. Med. Chem. Lett. 2008,
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m ;
max 2922, 2851, 1728, 1617, 1487, 1467, 1361, 1235, 1178, 900, 747 cmꢀ1 1H
NMR (400 MHz, CDCl3) d = 0.96–1.05 (m, 1H, CH2), 1.18–1.25 (m, 2H, CH2),
1.47–1.61 (m, 3H, CH2), 1.61–1.70 (m, 1H, CH2), 1.75–1.83 (m, 1H, CH2), 3.29–
3.33 (m, 1H, N–CH2), 3.88 (t, 2H, J = 4.8 Hz, OCH2), 4.19 (td, 1H, J1 = 14 Hz,
J2 = 4.8 Hz, N–CH2), 4.51 (s, 1H, OCH), 6.74 (d, 1H, J = 8.0 Hz, ArH), 6.86 (d, 1H,
J = 7.6 Hz, ArH), 6.96 (t, 1H, J = 8.0 Hz, ArH), 7.04 (t, 1H, J = 7.6 Hz, ArH), 7.16 (d,
1H, J = 8.0 Hz, ArH), 7.22–7.26 (m, 1H, ArH), 7.30 (td, 1H, J1 = 7.8 Hz, J2 = 1.2 Hz,
ArH), 7.54 (d, 1H, J = 7.2 Hz, ArH); 13C NMR (100 MHz, CDCl3) d 24.40 (CH2),
24.72 (CH2), 24.83 (CH2), 27.37 (CH2), 39.92 (CH2), 61.31 (quat-C), 64.04 (CH,
observed in DEPT-90 NMR) 64.79 (CH2), 109.21 (@CH), 110.55 (@CH), 120.45
(@CH), 121.88 (@CH), 122.06 (quat-C), 122.37 (@CH), 123.58 (quat-C), 129.03
(@CH), 129.45 (@CH), 129.90 (@CH), 143.89 (quat-C), 155.35 (quat-C), 170.46
18. Diazoamide 9a: 3-diazo-1,3-dihydro-2H-indol-2-one (8a) (1.5 g, 9.43 mmol)
and potassium carbonate (3.26 g, 23.57 mmol) were taken in dry DMF
under an argon atmosphere and stirred for 5 min. 2-(6-Bromohexyloxy)
benzaldehyde (3.2 g, 11.32 mmol) and
a catalytic amount of tetrabu-
tylammonium iodide were then added. The reaction mixture was allowed to
stir for 9 h to obtain 9a (90%) as a red liquid based on the general procedure. IR
(neat): mmax 2927, 2849, 1723, 1669, 1473, 1449, 1419, 1217, 1139, 735 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d = 1.33–1.37 (m, 2H, CH2), 1.38–1.46 (m, 2H, CH2),
1.61–1.67 (m, 2H, CH2), 1.70–1.77 (m, 2H, CH2), 3.72–3.76 (t, 2H, J = 7.2 Hz, N–
CH2), 3.93–3.96 (t, 2H, J = 6.4 Hz, OCH2), 6.83–7.10 (m, 6H, ArH), 7.39–7.43 (m,
1H, ArH), 7.70–7.72 (dd, 1H, J1 = 7.6, J2 = 1.2 Hz, ArH), 10.38 (s, 1H, OCH); 13C
NMR (100 MHz, CDCl3) d 25.70 (CH2), 26.48 (CH2), 27.92 (CH2), 28.90 (CH2),
(quat-C); HRMS (ESI) calcd for
358.1413.
C
21H21NNaO3 [M+Na]+ 358.1423; found,