Preparation of benzoheterocyclic carbaldeydes

Article abstract of DOI:10.1016/j.tetlet.2008.11.066

The preparation of benzoheterocyclic carbaldehydes in the 2-amino-substituted benzothiazole, benzoxazole and benzimidazole series is described. Starting with the methyl-substituted 2-aminobenzoheterocycle, the nitrogen is protected as an N,N-diBoc derivat

Full text of DOI:10.1016/j.tetlet.2008.11.066

Tetrahedron Letters 50 (2009) 580–583
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Preparation of benzoheterocyclic carbaldeydes q
*
Frederick A. Luzzio , Marek T. Wlodarczyk
Department of Chemistry, University of Louisville 2320 South Brook Street, Louisville, KY 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of benzoheterocyclic carbaldehydes in the 2-amino-substituted benzothiazole, benzox-
azole and benzimidazole series is described. Starting with the methyl-substituted 2-aminobenzohetero-
cycle, the nitrogen is protected as an N,N-diBoc derivative. Next, free radical halogenation of the methyl
group with NBS/AIBN affords the N(Boc)2-protected benzylic dibromide which is directly used in the final
step. A mild silver nitrite/dimethylsulfoxide-mediated conversion of the dibromide to the aldehyde func-
tionality completes the process.
Received 10 October 2008
Accepted 19 November 2008
Available online 24 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Benzoheterocycles such as benzothiazoles, benzimid azoles and
benzoxazoles can serve as unique and versatile scaffolds for exper-
imental drug design as exemplified by the structures of riluzole,Ò2
dabigatranÒ3 and flunoxaprofen,Ò4 and the vanillanoid receptor-1
(VR1) antagonist AMG 6285 (Fig. 1). For structural elaboration in
lead optimization, the points of attachment on the benzoheterocy-
cle can be through a number of atoms on either the benzene or het-
erocyclic rings and can take the form of ether, sulfide, amide, amine
or carbon–carbon bonds. In general, the formation of heteroatom
linkages between any point on the benzoheterocyclic nucleus and,
for example, any aromatic, lipid-like, peptide, heterocyclic or even
carbohydrate appendage may take advantage of O, S, N nucleophi-
licity (see riluzole and AMG 628, Fig. 1). However, the formation
of carbon–carbon bonds to the benzoheterocyclic nucleus from
these appendages may be more involved, particularly in the pres-
ence of sensitive heteroatom functionality on the heterocyclic por-
tion of the nucleus. Such structures are exemplified in the
benzothiazole series that include the b2-adrenoceptor agonist
S13196 and the dual D2–b2 receptor agonist, sibenadet (Fig. 1).7
For example, palladium chemistry may be envisioned to facilitate
the formation of a carbon linkage between a suitably halogenated
benzo-heterocyclic nucleus and the coupling partners activated
via C-organometal (aryl or alkyl) derivatives (Scheme 1). A similar
alternative may entail the reaction of a halomethyl derivative of
the benzoheterocycle and a C-organometal coupling partner with
transition metal mediation. A more involved strategy, albeit with
the same end in mind, might be to formylate the appropriately-pro-
tected metalated benzoheterocycle followed by submitting the
resulting aldehyde to the reliable and vastly numerous carbon–car-
bon bond forming reactions of aldehydes (Scheme 1). The coupling
reaction, of course, would depend on the structure of the coupling
partner, the protecting groups present and the synthetic target
desired. The main issue to address when pursuing the metalation-
formylation approach is the lack of ready availability of a reliable
and robust amine protecting group which is compatible with the
requisite carbanion chemistry and subsequent C–C bond formation
reactions. Our approach to the synthesis of benzoheterocyclic alde-
hydes is with the ultimate goal of single-step carbon–carbon bond
formation so that scaffolds with benzoheterocyclic C-aryl and C-al-
kyl cores may be prepared (Scheme 2). Hence, we required aldehyde
intermediates since these derivatives may be used in numerous reli-
able, high-yield and scalable reactions so that the desired carbon-
linked core structures may be obtained. Our scheme begins with
N-protected benzoheterocycles having a specifically-positioned
methyl that is the procarbonyl carbon which will be converted to
the aldehyde intermediate via a halo or dihalo intermediate. When
viewing the overall transformation of an arylmethyl group to an
aldehyde or carboxylic acid, one would immediately surmise that
any number of direct oxidants will accomplish the same. However,
the presence of oxidant-sensitive heteroatoms such as nitrogen and
sulfur that make up the ring system, as well as any additional nitro-
gen appendages, will complicate the formation of the desired prod-
ucts and render the task far more demanding. Earlier studies by a
Wyeth group entailed the benzylic free-radical bromination of an
N-protected-2-methylindole nucleus followed by a DMSO-medi-
ated conversion of the resultant dibromide to the desired aldehyde.8
Another report by a Novartis group encompassed the free-radical
benzylic dibromination of a 2-adamantyl-substituted-6-methyl
chromenone followed by hydrolysis to the dialdehyde with potas-
sium acetate/acetic acid.9,10 In both cases the isolated methyl group
on the aryl portion of the benzoheterocyclic system was converted
to the corresponding aldehydes under conditions which did not re-
quire harsh oxidants. Accordingly, we developed a multistep, albeit
milder version of the above-cited methods for the preparation of
benzoheterocyclic carbaldehydes having two heterocyclic atoms
and a protected nitrogen appendage. The method does not employ
q
See Ref. [1].
* Corresponding author. Tel.: +1 502 852 7323; fax: +1 502 852 8149.
E-mail address: faluzz01@gwise.louisville.edu (F.A. Luzzio).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.066

F. A. Luzzio, M. T. Wlodarczyk / Tetrahedron Letters 50 (2009) 580–583
581
O
S
O
Ph
HO
NH
S
NHCH3
O
F3C
S
CH3
O
O
O
O
N
S
N
H
HOOC
N
H
F
NH2
OH
OH
N
sibenadet HCl
S1319
flunoxaprofen
riluzole
O
N
O
N
CH3
H
N
AcHN
N
N
N
S
O
N
N
N
O
F
O
N
N
NH2
O
dabigatran
AMG 628
Figure 1.
NH2
R
R=OH
R=NH2
N
R
I,Br
Br-CN
X
Y
H3C
X
NH2
H3C
H3C
1. metalate
2. formylate
NR2
NR2
OHC
MeOH/CH2Cl2
Y
2a, 2b: R=O
2g: R=NH, 5-Me
R=NH, 6-me
various C-C
X, Y=heteroatoms
R=protecting group
forming
reactions
H
N
NH2
X
Y
N
RCH2M
Pd cat
NBS
NR2
H3C
RH2C
NH2
S
S
AcOH
2c-f
Scheme 1.
Scheme 3.
harsh oxidants or high temperatures and is proven to be compatible
with amine protection.
The preparation of the starting heterocycles is straightforward
and can be accomplished in relatively large scale with commer-
crystalline materials in modest to excellent yields. The lone
exception is the benzimidazole 2g which afforded a mixture of
the 5- and 6-methyl tri-Boc derivatives 3g. The resulting N,N-diBoc
compounds 3a–g are then converted to the dibromomethyl 2-N,N-
diBoc products 4a–g by treatment with N-bromosuccinimide
(NBS) in tetrachloromethane (CCl4) with initiation by 2, 20-azobis-
isobutyronitrile (AIBN). Although the free radical bromination step
to the dibromide is run under relatively mild conditions, it is nec-
essary to fully protect the nitrogen otherwise decomposition and
unwanted side products predominated as preliminary experiments
revealed.13 Interestingly, our original plan was to monobrominate
the methyl group followed by direct conversion to the aldehyde by
a displacement-oxidation protocol using a metal nitrate.14 How-
ever, we found that monobromination to the bromomethyl inter-
mediate was difficult to control thereby giving substantial
amounts of dibromide before the starting methyl compounds were
consumed. In turn, tribromination of the benzylic methyl group
may be minimized or avoided by carefully monitoring the reaction
by 1H NMR, and since the brominations are run in CCl4, the reac-
tion mixture may be directly sampled for spectral analysis without
solvent removal or workup. Overall, we found that the dibromide
intermediates necessitated minimal separation from the by-prod-
ucts and components of the free-radical reactions. The yields of
the intermediate dibromides are listed in Table 2. Next, an efficient
protocol for the direct conversion of the more controllable, higher-
yielding dibromides 4a–g to the aldehydes 1a–g (Table 2) was pur-
sued. A number of factors influenced our choice of the nitrite ion in
the conversions of 4a–g to the title compounds. In practice, a
straightforward base-mediated hydrolysis is all that is required
for the conversion of a typical aryldibromide to a benzaldehyde.15
However, any form of base would also work to the detriment of the
N(Boc)2 group, present in our compounds, and result in complex
product mixtures due to partial N-deprotection. We presumed that
the benzylic carbon, with its gem-dibromo substitution, would
have a high carbonium ion-like reactivity and would be ideal for
cially-available
compounds.
2-Aminomethyl-substituted
benzoxazoles or benzimidazoles were prepared by reaction of
methyl-substituted o-aminophenols or o-diamines with cyanogen
bromide while the corresponding benzothiazoles can be prepared
by halogen-mediated cyclization of methyl-substituted N-phen-
ylthioureas (Scheme 3). The relative inertness of the methyl group
allows a great many possibilities in generating the starting hetero-
cycle before conversion to the title aldehydes especially in cases
where halogenative ring closure of N-substituted thioureas was
the only route to the corresponding benzothiazoles. Our synthetic
scheme starts with N,N-diBoc protection of the 2-amino substitu-
ent of the heterocycle as depicted in Scheme 2.11 In reviewing
the literature for cases of effective N-protection of substrates
which are to undergo subsequent free-radical halogenation, we
found that free radical benzylic bromination of amino acids pro-
tected as their N,N-diBoc derivatives was successful.12 Treatment
of the methyl-substituted-2-aminobenzo-heterocycles 2a–g with
Boc carbonate and triethylamine or 4-dimethylaminopyridine
(DMAP) provides the N,N-diBoc compounds 3a–g (Table 1) as
N
X
(t-BuO)2CO
N
X
H3C
NH2
H3C
NBoc2
DMAP
CH2Cl2
R
R
2a-g
3a-g
X=N, O, S
NBS/AIBN
R=4-Cl, 4-MeO
CCl4/Δ
N
AgNO2
N
X
O
Br2HC
NBoc2
NBoc2
DMSO
X
H
PhCH3/Δ
R
R
1a-g
4a-g
Scheme 2.

582
F. A. Luzzio, M. T. Wlodarczyk / Tetrahedron Letters 50 (2009) 580–583
Table 1
Table 2
DiBoc protection of 2-aminobenzoheterocycles
Preparation of the benzoheterocyclic aldehydes from the dibromides
Substrate
DiBOC Product
Yielda,b (%)
Dibromide (%)a
Yield (%)
Aldehyde
Yieldb (%)
87
CH3
N
CH3
N
CHBr2
N
CHO
N
97
77
NH2
N(Boc)2
N(Boc)2
N(Boc)2
N
O
O
O
O
1a
4a
Br2HC
2a
3a
H3C
H3C
N
O
N
O
OHC
N
O
NH2
N(Boc)2
52
94
N(Boc)2
N(Boc)2
80
70
52
99
O
2b
3b
1b
4b
CH3
N
CH3
CHBr2
CHO
N
N
S
N
NH2
NH2
N(Boc)2
N(Boc)2
N(Boc)2
N(Boc)2
N(Boc)2
N(Boc)2
S
S
S
2cc
3c
1c
4c
CH3
S
CH3
CHBr2
CHO
S
S
N
S
97
85
74
93
N
OCH3
2d
CH3
N
N
N
OCH3
3d
CH3
OCH3
4d
OCH3
1d
CHBr2
CHO
N
N
S
N
NH2
N(Boc)2
N
N(Boc)2
N(Boc)2
N
83
46
49
95
93
77
S
S
S
Cl
2e
Cl
3e
Cl
4e
Cl
1e
N
S
N
S
N(Boc)2
N(Boc)2
N(Boc)2
NH2
NH2
N(Boc)2
75
71
S
S
Br2HC
OHC
OHC
H3C
H3C
H3C
2f3
3f
1f
4f
N
N
N
N
N
N
N
N(Boc)2
N(Boc)2
Boc
N
H
H3C
Br2HC
Boc
Boc
2gd
3gd
1gc
4gc
aIsolated, purified yield from the corresponding 2-aminobenzoheterocycle.
bCompounds were fully characterized by 1H, 13C NMR, IR and HRMS.
cCommercially-available starting materials.
aCharacterized by 1H and 13C NMR but used directly in the next reaction.
bYields of title compounds are of isolated, purified products.
cMixture of chromatographically homogeneous 5-dibromomethyl (4g) and 6-
formylbenzoimidazole-2-amine derivatives (1g).
dMixture of chromatographically homogeneous 5- and 6-methylbenzo imidazole-2-
amine (2g) and corresponding N-Boc derivatives (3g).
introduction of oxygen through the ambident nitrite ion.16,17 The
decomposition of any intermediate gem-dinitrite, formed through
the silver-promoted bis-substitution, will then result in aldehyde
formation. Given that silver nitrite is very difficult to render strictly
anhydrous, any adventitious water will play a positive role in the
decomposition of intermediate nitrite esters. Furthermore we
anticipated that the N(Boc)2 group should be relatively stable to
the released nitrous acid thereby ensuring the survival of the title
compounds in the final reaction. Hence, direct submission of the
2- N,N-diprotected dibromomethyl intermediates 4a–g to silver
nitrite in a two-phase system of dimethylsulfoxide (DMSO)/tolu-
ene afforded the corresponding title benzoheterocyclic aldehydes
1a–g in yields of 52–99% (Table 2).
after chromatographic purification. Finally, exposure of aldehyde
1d to n-butyllithium (1 equiv, ꢀ78 ?rt) gave the –N(Boc)2 hetero-
cyclic carbinol 10 in 50% yield accompanied by the –N(Boc) alcohol
10a (30%) which had suffered partial deprotection.
COOEt
HO
S
N
NO2
N
N(Boc)2
N
S
N(Boc)2
N(Boc)2
OCH3
EtOOC
O
6
5
7
Some of the –N(Boc)2 heterocyclic aldehydes were probed for
their response to several fundamental carbon–carbon forming
reactions, in part to evaluate the robustness of the diBoc group,
and to introduce new structural motifs bearing the benzoheterocy-
clic core. Aldehydes 1d and 1f were treated with freshly-prepared
ethoxycarbonyl methylidenetriphenylphosphorane (19 h, rt) to
give olefinic esters 5 and 6 in 85% and 76% yields, respectively after
chromatographic purification. En route to the preparation of S1319
(Fig. 1) analogues,6,18 submission of aldehydes 1a and 1e to the
Henry reaction using nitromethane (10 equiv, 1–5 h, rt) in THF
gave both the corresponding nitroalcohols 7 and 8 in 97% and
75% isolated yield, respectively. Treatment of aldehyde 1d with
freshly-prepared phenylmagnesium bromide (0.68 M, 1.1 equiv, 0
?rt) gave the –N(Boc)2 heterocyclic biarylmethanol 9 in 84% yield
HO
R
S
HO
NO2
NR1R2
N
N
N(Boc)2
OCH3
S
9, R=Ph, R1=R2=Boc
Cl
10, R=C4H9-n, R1=R2=Boc
10a, R=C4H9-n, R1=Boc, R2=H
8
In summary, we have detailed an efficient synthesis of N-substituted
arylcarbaldehydes in the N-protected 2-aminobenzoheterocyclic
series using a three-step sequence. The sequence employs methyl-
substituted 2-aminobenzo heterocycles effectively protected as their
stable N,N-diBoc derivatives. Carefully controlled free-radical

F. A. Luzzio, M. T. Wlodarczyk / Tetrahedron Letters 50 (2009) 580–583
583
Ganul, P.; Gueremy, C.; Honore, R.; Just, B.; Kerpherique, R.; Gontier, S.; Hubert,
P.; Laduron, P. M.; LeBlevec, J.; Meunier, M.; Miquet, J.-M.; Nemecek, C.; Pasquet,
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Chem. 1999, 42, 2828–2843.
benzylic dibromination of the methyl group followed by direct con-
version of the reactive product dibromides to the corresponding title
compoundswithsilvernitrite/DMSOcompletestheoverallschemein
modest to high yields. Most notably, only the combination of the
N(Boc)2 protection and the nitrite substitution allowed the overall
scheme to be successful with the substrates at hand. The multi-step
route was the best immediate alternative to the use of harsh oxidants
which are historically used to prepare arylaldehydes from relatively
robust arylmethyl compounds. In considering the overall utility of
the sequence in carbon–carbon bond formation using aldehydes,
the route proves to be an excellent, reliable alternative to transition
metal and organometal coupling reactions. Application of the scheme
to the synthesis of novel pharmacophores and natural products is
underway and the results will be reported in due course.
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K. J. Am. Chem. Soc. 1956, 78, 1689–1692; Baraldi, P. G.; Budriesi, R.; Cacciari, B.;
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Acknowledgments
Support of the Mass Spectrometry Facility of the University of
Louisville CREAM Center by NSF/EPSCOR Grant EPS-0447479 is
gratefully acknowledged. We thank Dr. Rick Higashi for the HRMS
determination of the new compounds and Ms. Juan Chen for tech-
nical assistance.
A. Supplementary data
14. For a procedure where the conversion of a methyl group to an aldehyde or a
carboxylic acid is facilitated through a monobromide see: Deady, L. W.; Devine,
S. M.; Rogers, M. L. Org. Prep. Proced. Int. 2003, 35, 627–630; For the related
Kornblum oxidation of alkyl and benzyl halides and tosylates to aldehydes see:
Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113–
4114.
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Johnstone, A. J. Chem. Technol. Biotechnol. 1998, 71, 111–120.
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Int. Ed. Engl. 2005, 44, 4623–4626.
Experimental procedures, product characterization and 1H and
13C spectra for compounds 1a–g and 3a–g. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.11.066.
References and notes
1. Presented at the 235th National Meeting of the American Chemical Society,
New Orleans, LA; April 6–10, 2008.
2. Jimonet, P.; Audiau, F.; Barreau, M.; Blanchard, J.-C.; Boireau, A.; Bour, Y.; Coleno,
M.-A.; Doble, A.; Doerflinger, G.; Huu, C. D.; Donat, M. H.; Duchesne, J. M.;
17. Olah, G. A.; Ramaiah, P. J. Org. Chem. 1993, 58, 4639–4641.
18. The preparation of S1319 analogues, using the scheme described herein will be
communicated separately.