α-formylation of α-substituted ketones

Article abstract of DOI:10.1055/s-0031-1290121

The reaction of (chloromethylene)dimethylammonium chloride (generated in situ from oxalyl chloride and DMF) with α-substituted ketones in CH ₂Cl₂, followed by workup with aqueous NaHCO₃, gave β-keto aldehydes containing an

Full text of DOI:10.1055/s-0031-1290121

LETTER
239
a-Formylation of a-Substituted Ketones
a
-Formyla
a
tion of
a
-
Su
m
bstituted Ketone
s
al Hassan, Christopher J. Richards*
School of Chemistry, University of East Anglia, Norwich, NR4 7TJ, UK
Fax +44(1603)592003; E-mail: Chris.Richards@uea.ac.uk
Received 1 November 2011
cedure are limited to the reaction of DMF/POCl3 with O-
silylated enolates of carboxylic esters.7 In this Letter we
report on the one-step conversion of a-substituted ketones
into a-formyl-a-substituted ketones by reaction with
Vilsmeier reagent 1.
Abstract: The reaction of (chloromethylene)dimethylammonium
chloride (generated in situ from oxalyl chloride and DMF) with a-
substituted ketones in CH2Cl2, followed by workup with aqueous
NaHCO3, gave b-keto aldehydes containing an a-quaternary centre
(8–88% yield).
Key words: aldehydes, enols, hydrolysis, ketones, tautomerism
The ketone a-formylation methodology was first exam-
ined with the addition of a-methylindanone 5 derived silyl
enol ether 6 to three equivalents of in situ generated
Vilsmeier salt 1. After stirring at room temperature for 24
hours, addition of aqueous saturated sodium hydrogencar-
bonate resulted in the formation of a-formyl product 7
(Scheme 2). This procedure was also applied to the a-me-
thyltetralone 8 derived silyl enol ether 9, albeit resulting
in a lower conversion to the a-formyl product 10.
The Vilsmeier–Haack formylation is a simple procedure
for the functionalisation of electron-rich aromatic com-
pounds.1 The method requires the generation of an elec-
trophilic (chloromethylene)ammonium salt (a Vilsmeier
reagent) from the reaction of N-methylformanilide or
DMF with either POCl3, SOCl2, COCl2, or (COCl)2.2 The
use of DMF/oxalyl chloride is especially convenient,3 and
the resulting chloroiminium salt 1 (Scheme 1) has found
many other applications in organic synthesis. These in-
clude its use as an alcohol-activating reagent for subse-
quent nucleophilic substitution,4 a carboxylic acid
activator in the Staudinger reaction,5 and the conversion
of carbonyl compounds of general structure R1COCH2R2
into b-chloroenals R1ClC=C(CHO)R2.6
OTMS
O
i) DMF (3 equiv), (COCl)2
CH2Cl2, r.t., 24 h
CHO
ii) sat. NaHCO3 (aq)
n
n
6 n = 1
9 n = 2
7 n = 1 (63%)
10 n = 2 (13%)
Scheme 2 Reaction of silyl enol ethers with in situ generated (chlo-
romethylene)dimethylammonium chloride 1
O
R1
During the course of these studies we discovered that pre-
formation of the silyl enol ether was not required; direct
use of a-methylindanone 5 under the same conditions re-
sulted in an essentially quantitative conversion to a-
formyl product 7 (Scheme 3, Table 1, entry 1). Mirroring
the results obtained with the silyl enol ethers, the use of a-
methyltetralone 8 resulted in a lower yield of formylated
product (Table 1, entry 2). Further examination of this
less reactive substrate with the Vilsmeier salt derived
from POCl3 did not improve the yield (Table 1, entry 3),
and generation of (bromomethylene)dimethylammonium
salts8 from (COBr)2 (Table 1, entry 4) and POBr3
(Table 1, entry 5) did not result in a-formylation. As the
use of triflic anhydride/DMF has been applied to the
formylation of less active aromatics,9 we also examined
this combination resulting in the isolation of the corre-
sponding enol triflate (Table 1, entry 6). Reverting to in
situ generated 1, and heating at reflux the reaction mix-
ture, resulted in a 83% conversion to the a-formylated
product 10 (Table 1, entry 7). Using these conditions with
reaction times longer than 24 hours did not increase the
conversion; instead products resulting from O-formyla-
tion were observed.
(COCl)2
CH2Cl2
Me
O
Me
R3
N
R2
2
i)
Me
Cl
Me
Cl
N
OX
O
1
R1
CHO
R3
R3
(– XCl)
R2
R1 R2
4
ii) NaHCO3 (aq)
3
R1, R2 ≠ H
X = SiR3, H
Scheme 1 Proposed procedure for the a-formylation of a-substitu-
ted ketones
Another potential reaction of 1 is with an activated alkene
derived from an a-substituted carbonyl 2 following its
conversion into an enol or enol derivative 3. Subsequent
hydrolysis of the addition product will give 4, a homolo-
gated species containing a quaternary centre. To the best
of our knowledge literature examples of this general pro-
SYNLETT 2012, 23, 239–242
x
x.
x
x.
2
0
1
1
No a-formylation was observed when the reaction was
performed in toluene, THF, or Et2O, solvents in which 1
Advanced online publication: 22.12.2011
DOI: 10.1055/s-0031-1290121; Art ID: D61711ST
© Georg Thieme Verlag Stuttgart · New York

240
J. Hassan, C. J. Richards
LETTER
O
the a-formylation product
7
and chloroenal 22
O
i) DMF (3 equiv), A
(Scheme 4). The suitability of a-substituted aromatic cy-
clic ketones towards this simple a-formylation reaction is
likely a function of the position of keto–enol equilibrium
under the acidic reaction conditions employed.
CHO
CH2Cl2, 24 h
ii) sat. NaHCO3 (aq)
n
n
5 n = 1
8 n = 2
7 n = 1
10 n = 2
Scheme 3 Investigative a-formylation reactions of a-methyl keto-
nes 5 and 8
O
O
CHO
i) DMF (1 equiv), (COCl)2
CH2Cl2, 24 h
Table 1 Investigative a-Formylation Reactions of a-Methyl
Ketones 5 and 8a
5
7 (68%)
O
Cl
ii) sat. NaHCO3 (aq)
Entry
Ketone Temp (°C) Reagent A
Conversion (%)b
CHO
1
2
3
4
5
6
7
8e
5
8
8
8
8
8
8
8
20
20
20
20
20
20
38
62
(COCl)2
(COCl)2
POCl3
>99
19
10
0c
22 (32%)
21
Scheme 4 Competitive a-formylation vs. chloroenal formation
The decarbonylation of tertiary aldehydes under mild ox-
idative conditions is proposed to occur via initial forma-
tion of an acyl radical and subsequent loss of carbon
monoxide.11 Neither air compared to N2, or light com-
pared to dark, however, were found to have an influence
on the stability of 10 towards decarbonylation. In contrast,
silica added to a solution of 10 in CDCl3 was found to pro-
mote decarbonylation. We also noted a correlation be-
tween the reactivity of the a-substituted ketone towards a-
formylation, and the propensity of the product obtained to
undergo decarbonylation back to the starting material.
(COBr)2
POBr3
0c
Tf2O
0d
(COCl)2
(COCl)2
83
74
a All reaction times = 24 h, in CH2Cl2 unless otherwise stated.
b Determined by 1H NMR.
c Recovery of starting ketone.
d Formation of 2-methyl-3,4-dihydronaphthalen-1-yl trifluoro-
methanesulfonate.10,
The a-formylation products may be used directly avoid-
ing chromatography. This was demonstrated by reductive
amination with benzylamine and NaBH(OAc)3 to give
stable aminoketones 23 and 24 (Scheme 5).
e In CHCl3.
is insoluble. Chloroform may be employed as an alterna-
tive to dichloromethane, although the higher reaction tem-
perature permitted did not result in an increase in yield
compared to the use of dichloromethane at reflux
(Table 1, entry 8).
O
O
i) 1 (3 equiv), CH2Cl2
24 h, r.t. or 38 °C
N
Ph
H
ii) sat. NaHCO3 (aq)
iii) BnNH2, DCE
NaBH(OAc)3
n
n
The preparative synthesis of a-formyl-a-substituted ke-
tones began with the isolation of 7 in good yield following
aqueous workup (Table 2, entry 1). Attempted Kugelrohr
distillation resulted in appreciable decarbonylation and
regeneration of a-methylindanone. Conversion to the ben-
zyl analogue 12 was also good (Table 2, entry 2), but
chromatography on SiO2 with 10% EtOAc–hexane result-
ed only in the recovery of the starting material 11. This
was also the outcome on addition of 2% Et3N to the col-
umn solvents. Conversely, addition of 2% formic acid to
10% EtOAc–hexanes did enable the isolation of some of
the product. This method of isolation was also applied to
the isolation of the tetralone derivatives 10 and 14
(Table 2, entries 3 and 4). 2-Phenyltetralone (15) resulted
in O-formylation (Table 2, entry 5). Reaction of acyclic
ketone 17 was significantly slower giving a low conver-
sion and thus low yield of 18 (Table 2, entry 6) In contrast,
the use of the nonaromatic ketone 19 resulted in a signifi-
cantly higher yield of the mono-a-formyl ketone 20
(Table 2, entry 7). Finally, a competition experiment be-
tween a-methylindanone 5 and indanone 21 with one
equivalent of 1 resulted in an approximately 2:1 ratio of
5 n = 1
8 n = 2
23 n = 1 (39%)
24 n = 2 (24%)
Scheme 5 Reductive amination of a-formylation products
In summary, we have demonstrated the simple one-pot
conversion of a-substituted ketones into homologated a-
formyl-a-substituted ketones. Cyclic aryl ketones in par-
ticular give good conversions, and if chromatography on
silica is avoided, good yields of bifunctional building
blocks containing a quaternary centre.
2-Methyl-1-oxoindane-2-carbaldehyde (7)
To a solution of DMF (1.29 mL, 16.6 mmol) in dry CH2Cl2 (50 mL)
was added dropwise oxalyl chloride (1.43 mL, 16.6 mmol), and the
solution was stirred under argon for 1 h at 0 °C during which time
the solution turned pale yellow. Then 2-methyl-1-indanone (0.810
g, 5.54 mmol) was added, and the reaction mixture was stirred at r.t.
for 24 h. The reaction was quenched by the addition of sat. aq
NaHCO3 (20 mL) with stirring. The CH2Cl2 was removed in vacuo,
and the remaining aqueous phase was extracted with a mixture of
pentane (200 mL) and Et2O (30 mL). Following removal of the
Synlett 2012, 23, 239–242
© Thieme Stuttgart · New York

LETTER
a-Formylation of a-Substitued Ketones
241
Table 2 Preparative a-Formylation Reactionsa
Entry
Temp (°C)
Ketone
Product
Conversion (%)b Yield (%)
O
O
O
CHO
1
r.t.
>99
89
88c
37d
5
7
O
CHO
Ph
2
3
4
r.t.
38
38
Ph
11
12
10
O
O
CHO
83
74
34d
8
O
O
CHO
45d
13
14
16
CHO
O
O
O
O
Ph
Ph
5
38
85
84d
15
CHO
6
7
38
38
11
59
8d
17
18
O
O
CHO
40d
19
20
a Conditions: 3 equiv of in situ generated 1, CH2Cl2, 24 h.
b Determined by 1H NMR.
c Isolated by aqueous workup.
d Isolated by column chromatography.
aqueous layer, the organic layer was washed with sat. aq NaHCO3
(2 × 100 mL), dried (MgSO4), filtered, and the solvent was removed
in vacuo to afford the desired material as a pale yellow oil (0.850 g,
88%). 1H NMR (300 MHz, CDCl3): d = 1.55 (3 H, s CH3), 2.85 (1
H, d, J = 17 Hz, CHH), 3.83 (1 H, d, J = 17 Hz, CHH), 7.37 (1 H, t,
J = 8 Hz, ArH), 7.45 (1 H, d, J = 8 Hz, ArH), 7.59 (1 H, t, J = 8 Hz,
ArH), 7.76 (1 H, d, J = 8 Hz, ArH), 9.59 (1 H, s, CHO). 13C NMR
(100 MHz, CDCl3): d = 18.9, 30.3, 62.7, 124.3, 126.5, 127.5, 134.3,
135.3, 152.4, 196.5, 202.4. IR (CH2Cl2): nmax = 1736, 1704, 1608,
1465, 1278 cm–1. HMRS (ES): m/z calcd for C11H11O2: 175.0754;
found: 175.0752 [MH+].
flux for 24 h. The reaction was then diluted with CH2Cl2 (20 mL)
and quenched by the addition of sat. aq NaHCO3 (20 mL). Follow-
ing separation, the aqueous layer was extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were dried (MgSO4), filtered,
and the solvent was removed in vacuo. Column chromatography
(SiO2) with 2% formic acid–5% EtOAc–hexane gave the product as
1
a colourless oil (202 mg, 34%). H NMR (300 MHz, CDCl3): d =
1.39 (3 H, s, CH3), 1.98 (1 H, ddd, J = 14, 8, 5 Hz, CHH), 2.48 (1
H, ddd, J = 14, 8, 5 Hz, CHH), 2.96–3.06 (2 H, m, CH2), 7.23 (1 H,
d, J = 8 Hz, ArH), 7.31 (1 H, t, J = 8 Hz, ArH), 7.49 (1 H, t, J = 8
Hz, ArH), 8.02 (1 H, d, J = 8 Hz, ArH), 9.73 (1 H, s, CHO). 13C
NMR (75 MHz, CDCl3): d = 18.3, 25.1, 29.3, 57.9. 127.0. 127.8,
128.9, 131.4, 134.1, 143.5, 197.5, 201.0. IR (CH2Cl2): nmax = 1724,
1671, 1600, 1455, 1304, 1225 cm–1. HRMS (ES): m/z calcd for
C12H13O2: 189.0910; found: 189.0909 [MH+].
2-Methyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbalde-
hyde (10)
To a solution of DMF (0.72 mL, 9.4 mmol) in dry CH2Cl2 (35 mL)
was added dropwise oxalyl chloride (0.80 mL, 9.4 mmol), and the
solution was stirred under argon for 1 h at 0 °C during which time
the solution turned pale yellow. Then 2-methyl-1-tetralone (0.500 g,
3.12 mmol) was added, and the reaction mixture was heated at re-
Preparation of 2-(benzylamino)methyl-2-methylindan-1-one
Crude 2-methyl-1-oxoindane-2-carbaldehyde, generated as de-
scribed above from 2-methylindanone (0.210 g, 1.44 mmol), was
© Thieme Stuttgart · New York
Synlett 2012, 23, 239–242

242
J. Hassan, C. J. Richards
LETTER
Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron
dissolved in DCE (10 mL), and to the solution was added benzy-
lamine (0.16 mL, 1.5 mmol), sodium triacetoxyborohydride (0.375
g, 1.8 mmol) and AcOH (0.08 mL, 1.4 mmol), and the reaction mix-
ture was stirred under argon for 24 h at r.t. The reaction was then
quenched by the addition of sat. aq NaHCO3 (20 mL). Following
separation, the aqueous layer was extracted with CH2Cl2 (3 × 100
mL). The combined organic fractions were dried (MgSO4), filtered,
and the solvent was removed in vacuo. Column chromatography
(SiO2) with 3% MeOH– CH2Cl2 gave the product as a light brown
oil (0.150 g, 39%). 1H NMR (400 MHz, CDCl3): d = 1.12 (3 H, s,
CH3), 2.56 (1 H, d, J = 12 Hz, CHH), 2.77 (1 H, d, J = 17 Hz, CHH),
2.87 (1 H, d, J = 12 Hz, CHH), 3.23 (1 H, d, J = 17 Hz, CHH), 3.64
(1 H, d, J = 12, CHH), 3.69 (1 H, J = 12 Hz, CHH), 7.13–7.23 (5 H,
m, ArH), 7.28 (1 H, t, J = 8 Hz, ArH), 7.37 (1 H, d, J = 8 Hz, ArH),
7.51 (1 H, t, J = 8 Hz, ArH), 7.66 (1 H, d, J = 8 Hz, ArH). 13C NMR
(300 MHz, CDCl3): d = 22.8, 39.4, 50.4, 54.5, 55.9, 124.4, 126.9,
127.1, 127.5, 128.2, 128.5, 135.1, 136.4, 140.5, 153.7, 211.3. IR
(CH2Cl2): nmax = 1702, 1607, 1453, 1292 cm–1. HRMS (ES): m/z
calcd for C18H20NO: 266.1539; found: 266.1544 [MH+].
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Acknowledgment
We thank the EPSRC for support (JH) and the EPSRC National
Mass Spectrometry Centre (University of Wales, Swansea).
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Synlett 2012, 23, 239–242
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