A facile preparation of N-protected indolaldehydes using a modified Hass procedure

Article abstract of DOI:10.1016/j.tetlet.2005.09.121

The preparation of a variety of N-protected indolaldehydes is reported via the reaction of N-protected bromomethylindoles with 2-nitropropane using NaH/DMF.

Full text of DOI:10.1016/j.tetlet.2005.09.121

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8189–8193
A facile preparation of N-protected indolaldehydes
using a modified Hass procedure
Arasambattu K. Mohanakrishnan,* Ramalingam Balamurugan and Neelamegam Ramesh
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 17 June 2005; revised 14 September 2005; accepted 20 September 2005
Available online 6 October 2005
Abstract—The preparation of a variety of N-protected indolaldehydes is reported via the reaction of N-protected bromomethyl-
indoles with 2-nitropropane using NaH/DMF.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Indolaldehydes are crucial intermediates for the synthe-
sis of several indole alkaloids.1 While indole-3-carbox-
aldehyde can be prepared easily under conventional
Vilsmeier formylation conditions, aldehydes at other
positions of the indole ring are not easily accessible. Sev-
eral methods have been developed for the synthesis of
indolaldehydes and most are not scalable to any reason-
able extent.
aldehyde7 was realized through the reactions of the
corresponding bromomethylindole with DMSO in the
presence of NaHCO3. Our recent studies on the prepara-
tion of indolaldehydes using enamine methodology led
us to the synthesis of carbazoles.8
Hass and co-workers9 transformed a variety of substi-
tuted benzyl halides into the corresponding benzaldehy-
des using sodium-2-propane nitronate in ethanol. Later,
the methodology was extended to the synthesis of
heterocyclic and other carboxaldehydes10 except for
indolaldehydes.
Traditionally, indolaldehydes have been prepared from
the corresponding indolylmethanol via MnO2 oxida-
tion.2 Nagarathnam reported a synthesis of N-phenyl-
sulfonylindole-3-carboxaldehyde3 via hydrolysis of the
corresponding dibromomethylindole. Li et al. observed
a facile preparation of 1,3-disubstituted indole-2-carb-
oxaldehydes4 by the reactions of the corresponding
dibromomethylindole with DMSO. In that article, the
spectral data of the reported indolaldehyde was not
given nor was the reaction extended to the synthesis of
any other indolaldehydes. However, the methodology
has been well exploited for the synthesis of several
benzaldehydes.
Even though several methods have been introduced for
the conversion of benzyl halides into the corresponding
aldehydes most have yet to be explored for the indole
system. The synthetic utility of indolaldehydes and
also the availability of bromomethylindoles prompted
us to explore a viable procedure for the smooth transfor-
mation of bromomethylindoles into the respective
aldehydes.
Initially, the bromo compound 1a0 was reacted with
NaHCO3 in dry DMSO at 60 ꢁC for 2 h. The usual
workup followed by mass spectral analysis of the crude
product indicated the formation of aldehyde 2a [M+,
299] and alcohol 3 [M+, 301] as a mixture (Scheme 1).
The synthesis of the highly expensive indole-7-carboxal-
dehyde was realized through the Bartoli protocol.5 Srini-
vasan and co-workers recently observed the synthesis of
N-protected indolaldehydes through the reactions of
bromomethylindole6a with tetrabutylammonium dichro-
mate.6b A simple synthesis of N-tosylindole-4-carbox-
All the conditions tried for the oxidation of bromo-
methylindole 1a0 using dry DMSO in the presence of
NaHCO3 yielded the corresponding indolylmethanol 3
as a side product. Hence we decided to explore the
sodium-2-propane nitronate technique for the oxidation
Keywords: Bromomethylindoles; Sodium-2-propane nitronate;
Indolaldehydes.
*
Corresponding author. Tel.: +91 44 24451108; fax: +91 44
22352494; e-mail: mohan_67@hotmail.com
of
N-phenylsulfonyl-3-methyl-2-bromomethylindole.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.121

8190
A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 8189–8193
Me
Me
CHO
NaHCO3/DMSO
60 oC, 2 h
Me
CH2OH
Br
N
N
N
SO2Ph
SO2Ph
SO2Ph
1a'
2a
3
Scheme 1.
Me
Me
Me
Me
Me
CHO
Me
CHO
Me
CH2OCHO
O2N
O2N
Me
1a'
1a'
N
CHO
N
N
NaOEt/EtOH
rt, 10 h
Li2CO3/DMF
rt, 10 h
N
SO2Ph
SO2Ph
SO2Ph
H
2a
5
2a
4
Scheme 2.
Me
Me
O
N
Me
5
N
H
The reaction of the bromo compound 1a0 with sodium-
2-propane nitronate in ethanol at room temperature for
10h led to the formation of a mixture of the N-protected
and free aldehydes 2a and 4 in 40% and 25% yields,
respectively (Scheme 2).
SO2Ph
6
Scheme 3.
compound by the DMF to form the intermediate 6.
The latter on aqueous workup could lead to compound
5. However, the reaction of 2-nitropropane with Li2CO3
in DMF at 60 ꢁC for 2 h, followed by the addition of
bromo compound 1a0 led to the formation of the alde-
hyde 2a as the major product along with only a trace
amount of formate ester 5. Finally, the bromo com-
pound 1a0 was smoothly converted into the correspond-
ing aldehyde using the NaH/DMF conditions.
In particular, NaOEt being nucleophilic, had cleaved the
N-phenylsulfonyl unit. Additionally, in the ethanol sol-
vent, the reaction was found to be slow. Hence, we
decided to modify the reported Hass conditions by
changing the solvent/base.
The reaction of the bromo compound 1a0 with 2-nitro-
propane using Li2CO3 in DMF at room temperature
led to the isolation of the formate ester 5 in 56%
yield along with a minor amount of expected aldehyde
2a (Scheme 3). The formation of compound 5 can be
explained via nucleophilic displacement of the bromo
The various conditions tried and the products obtained
are presented in Table 1. In most cases, N-protected
aldehydes were obtained in reasonable yields with the
Table 1. Preparation of N-protected indolaldehydes using 2-nitropropane
Entry
Bromo/chloroindoles13
Conditions
Aldehydes14
Yield (%)a mp
Me
Me
X
1
NaH/DMF rt, 2 h
63 (210 ꢁC) 58
CHO
N
N
SO2Ph
SO2Ph
2a1g
1a' X = Br
1a" X = Cl
SPh
Br
SPh
CHO
2
NaOEt/EtOH rt, 24 h
NaH/DMF rt, 2 h
58 (110–112 ꢁC)
65 (112 ꢁC)
N
N
SO2Ph
SO2Ph
1b'
2b
SPh
SPh
Cl
CHO
3
4
NaH/DMF rt, 3 h
57 (112 ꢁC)
N
N
SO2Ph
SO2Ph
1b"
2b
Br
Br
Br
CHO
NaOEt/EtOH rt, 15 h
NaH/DMF rt, 4 h
42 (142 ꢁC)
65 (142 ꢁC)
N
N
SO2Ph
1c
SO2Ph
2c

A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 8189–8193
8191
Table 1 (continued)
Entry
Bromo/chloroindoles13
Conditions
Aldehydes14
Yield (%)a mp
0
CN
Br
CN
5
NaH/DMF rt, 15 h
CHO
N
N
SO2Ph
SO2Ph
2d
1d
MeO
MeO
CO2Et
CO2Et
CHO
Br
6
NaH/DMF rt, 2.5 h
57 (132–134 ꢁC)
N
N
SO2Ph
SO2Ph
2e
1e
CHO
Br
CO2Me
CO2Me
N
SO2Ph
7
8
NaH/DMF rt, 0.5 h
NaH/DMF rt, 0.5 h
66 (192 ꢁC)
N
SO2Ph
2f
1f
CO2Me
Br
CO2Me
CHO
61 (145–147 ꢁC)
N
N
H
SO2Ph
2g
1g
Br
CHO
9
NaOEt/EtOH rt, 15 h
NaH/DMF rt, 3 h
55 (102 ꢁC)
65
N
N
SO2Ph
2h
SO2Ph
1h
N
CO2Et
N
CO2Et
10
11
NaH/DMF rt, 0.5 h
NaH/DMF rt, 2 h
61 (54–56 ꢁC)
OHC
Br
2i
1i
CO2Me
Br
CO2Me
CHO
N
63 (134–136 ꢁC)
N
SO2Ph
SO2Ph
2j
1j
Br
Br
CHO
CHO
N
N
12
13
NaH/DMF rt, 3 h
NaH/DMF rt, 3 h
50(162–164 ꢁC)
SO2Ph
SO2Ph
2k2
1k
NO2
CHO
NO2
Br
65 (220 ꢁC)
N
N
OMe
OMe
SO2Ph
SO2Ph
OMe
OMe
1l
2l
a Isolated yield after column chromatography.
exception of bromo compound 1d where the oxidation
completely failed (entry 5). The dibromo compound 1k
led to the dialdehyde 2k in 50% yield (entry 12). The N-
protected indole-7-carboxaldehyde 2i1j was also prepared
in 61% yield (entry 10). It should be mentioned that in-
dole-7-aldehyde is used as a crucial starting material for
the synthesis of carbazole alkaloids.11 The reaction of
bromo compounds with 2-nitropropane using NaH/
DMF produced the corresponding aldehydes in much
better yields than the NaOEt/EtOH conditions. The oxi-
dation is much faster using the NaH/DMF conditions.
The N-protected chloromethylindoles 1a00 and 1b00 were
also converted into the respective aldehydes in reasonable
yields (entries 1 and 3). Even though the C-alkylation of
2-nitropropane anion is common to benzylic and hetero-
cyclic chloro compounds,12 we have not observed any
alkylation products with bromomethyl indoles.
In the case of bromo compound 1g, cleavage of the
N-phenylsulfonyl group was observed (entry 8). The

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A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 8189–8193
CO2Me
CO2Me
Me
Me
O
O
N
O
2g
N
Me
N
N
Me
OSO2Ph
SO2Ph
8
7
Scheme 4.
8. Mohanakrishnan, A. K.; Balamurugan, R. Tetrahedron
Lett. 2005, 37, 2659–2662.
9. Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71,
1767–1769.
cleavage of the N-protecting group in this case may be
due to the intramolecular interaction of the nitronate
anion with the N-phenylsulfonyl group to form the
intermediate 8, which on elimination may lead to the
N-free aldehyde 2g (Scheme 4).
10. (a) Brown, T. M.; Carruthers, W.; Pellatt, M. G. J. Chem.
Soc., Perkin Trans. 1 1982, 483–487; (b) Sha, C.-K.; Tsou,
C.-P.; Li, Y.-C.; Lee, R.-S.; Tsai, F.-Y.; Yeh, R.-H.
J. Chem. Soc., Chem. Commun. 1988, 1081–1083; (c) Sha,
C.-K.; Wang, D.-C. Tetrahedron 1994, 50, 7495–7502.
11. (a) Engler, T. A.; Furness, K.; Malhotra, S.; Diefenbacher,
C.; Clayton, J. R. Tetrahedron Lett. 2003, 44, 2903–2906;
(b) Kolis, S. P.; Clayton, M. T.; Grutsch, J. L.; Faul, M.
M. Tetrahedron Lett. 2003, 44, 5707–5710; (c) Zhu, G.;
Conner, S. E.; Zhou, X.; Chan, H.-K.; Shih, C.; Engler, T.
A.; Al-awar, R. S.; Brooks, H. B.; Watkins, S. A.; Spencer,
C. D.; Schultz, R. M.; Dempsey, J. A.; Considine, E. L.;
Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L.
Bioorg. Med. Chem. Lett. 2004, 14, 3057–3061.
12. Vanelle, P.; Gellis, A.; Kaafarani, M.; Maldonado, J.;
Crozet, M. P. Tetrahedron Lett. 1999, 40, 4343–4346.
13. The required bromo/chloroindoles 1a–l were prepared via
the allylic bromination/chlorination of the corresponding
methylindoles using NBS/NCS in the presence of a
catalytic amount of benzoyl peroxide in dry CCl4 at reflux.
14. Typical experimental procedure for 2b: A suspension of
50% NaH (78 mg, 1.64 mmol) in dry DMF (5 mL) was
treated with 2-nitropropane (0.2 mL, 2.19 mmol) at 0 ꢁC.
The mixture was stirred for 15 min at this temperature
under a nitrogen atmosphere and was treated dropwise
with a solution of bromo compound 1b0 (0.5 g, 1.09 mmol)
dissolved in dry DMF (3 mL). After the bromo compound
was consumed (monitored by TLC) the reaction mixture
was quenched with ice water (10mL), extracted with
In summary, the existing Hass procedure for the conver-
sion of benzylic halides into aldehydes has been
modified for the indole system. Using the modified
procedure, the synthesis of several N-protected indol-
aldehydes has been achieved in good yields. Hopefully,
the present procedure will be generally applicable to
the smooth conversion of benzylic halides into the corre-
sponding aldehydes. For the first time, a mild procedure
has been developed for the conversion of N-protected
bromomethylindoles into the indolylmethyl formate
ester using DMF. Further studies on the synthetic utility
of the indolaldehydes will be explored.
Acknowledgements
We thank UGC, New Delhi (F.12-140/2001 SR-1) for
the financial support. Financial support to the Depart-
ment by DST-FIST is also acknowledged.
References and notes
1. (a) Magnus, P.; Gallagher, T. Tetrahedron 1981, 37, 3889–
3897; (b) Magnus, P.; Gallagher, T.; Huffman, J. C. J. Am.
Chem. Soc. 1982, 104, 1140–1141; (c) Gribble, G. W.;
Saulnier, M. G.; Sibi, M. P.; Obaza-Nutaitis, J. A. J. Org.
Chem. 1984, 49, 4518–4523; (d) Hibino, S.; Sugino, E.;
Kuwada, T.; Ogura, N.; Sato, K.; Chosi, T. J. Org. Chem.
1992, 57, 5917–5921; (e) Sha, C.-K.; Yang, J. F. Tetra-
hedron 1992, 48, 10645–10654; (f) Love, B. E.; Raje, P. S.
J. Org. Chem. 1994, 59, 3219–3222; (g) Mohanakrishnan,
A. K.; Srinivasan, P. C. J. Org. Chem. 1995, 60, 1939–
1946; (h) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67,
9318–9330; (i) Kusurkar, R. S.; Goswami, S. K.; Vyas, S.
M. Tetrahedron Lett. 2003, 44, 4761–4763; (j) Kolis, S. P.;
Clayton, M. T.; Grutsch, J. L.; Faul, M. M. Tetrahedron
Lett. 2003, 44, 5707–5710.
CHCl3 (2 · 10mL) and dried (Na SO4). Removal of the
2
solvent, followed by column chromatographic purification
(silica gel, EtOAc–hexane 1:9) afforded 2b as a colorless
solid (0.28 g, 65%); mp 112 ꢁC; IR (KBr) mmax: 1654, 1562,
1492, 1373, 1180, 1080 cmꢀ1
.
1H NMR (400 MHz,
CDCl3): d 6.90(d, J = 7.8 Hz, 1H), 6.99–7.02 (m, 1H),
7.10–7.28 (m, 5H), 7.34 (t, J = 7.8 Hz, 2H), 7.40(t,
J = 3.4 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.70(d,
J = 7.3 Hz, 2H), 8.20(d, J = 8.3 Hz, 1H), 10.48 (s, 1H).
MS (EI) m/z (%): 393 (M+, 60%), 378 (75), 252 (89), 223
(88), 204 (100). Anal. Calcd for C21H15NO3S2: C, 64.10;
H, 3.84; N, 3.56; S, 16.30. Found: C, 64.41; H, 4.09; N,
3.65; S, 16.19.
Data for 2c: mp 142 ꢁC; IR (KBr) mmax: 1685, 1512, 1369,
2. Mohanakrishnan, A. K.; Srinivasan, P. C. Synth. Com-
mun. 1995, 25, 2407–2414.
3. Nagarathnam, D. J. Heterocycl. Chem. 1992, 29, 953–958.
4. Li, W.; Li, J.; DeVincentis, D.; Mansour, T. Tetrahedron
Lett. 2004, 45, 1071–1074.
1257, 1176, 1068 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
7.24–7.41 (m, 2H), 7.48–7.58 (m, 2H), 7.71–7.75 (m, 2H),
7.85 (d, J = 7.3 Hz, 1H), 8.17 (d, J = 8.3 Hz, 2H), 10.37 (s,
1H). MS (EI) m/z (%): 365 (M++, 15%), 363 (M+, 13) 333
(9), 256 (11), 224 (19), 105 (100). Anal. Calcd for
C15H10BrNO3S: C, 49.47; H, 2.77; N, 3.85; S, 8.80.
Found: C, 49.37; H, 2.93; N, 3.76; S, 8.73.
5. Dobson, D. R.; Gilmore, J.; Long, D. A. Synlett 1992, 79–
80.
6. (a) Suhana, H.; Srinivasan, P. C. Synth. Commun. 2003,
33, 3097–3102; (b) Mehta, G.; Panda, G. Tetrahedron Lett.
1997, 38, 2145–2148.
7. Muratake, H. H.; Natsume, M. Heterocycles 1999, 29,
783–794.
Data for 2h: mp 10 2ꢁC; IR (KBr) mmax: 1693, 1577, 1450,
1377, 1184, 1145 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d 7.36–7.43 (m, 4H), 7.48 (t, J = 7.3 Hz, 1H), 7.65
(d, J = 7.3 Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.79 (t, J =
4.4 Hz, 2H), 8.20(d, J = 8.3 Hz, 1H), 10.09 (s, 1H). MS

A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 8189–8193
8193
(EI) m/z (%): 285 (M+, 54%), 229 (18), 186 (20), 144 (17),
77 (100). Anal. Calcd for C15H11NO3S: C, 63.14; H, 3.89;
N, 4.91. Found: C, 63.05; H, 3.69; N, 4.94.
(EI) m/z (%): 217 (M+, 8%), 186 (11), 106 (41), 83 (40),
58 (100). Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10;
N, 6.45. Found: C, 66.48; H, 5.32; N, 6.43.
Data for 2i: mp 54–56 ꢁC; IR (KBr) mmax: 1739, 1672,
Data for 2l: mp 220 ꢁC; IR (KBr) mmax: 1660, 1500, 1250,
1
1
1315, 1041 cmꢀ1. H NMR (400 MHz, CDCl3): d 1.41 (t,
1360, 1160 cmꢀ1. H NMR (90MHz, CDCl 3): d 4.04 (s,
J = 7.3 Hz, 3H), 4.44 (q, J = 7.3 Hz, 2H), 6.66 (d,
J = 3.9 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.64 (d,
J = 3.9 Hz, 1H), 7.71–7.74 (m, 2H), 10.54 (s, 1H). MS
3H), 4.12 (s, 3H), 7.42–8.30(m, 13H), 1.014 (s, 1H).
Anal. Calcd for C25H20N2O7S: C, 60.97; H, 4.09; N, 5.69;
S, 6.51. Found: C, 61.23; H, 4.15; N, 5.58; S, 6.64.