Vilsmeier-Haack reaction of 1-cyclopropyl-2-arylethanones

Article abstract of DOI:10.1021/jo801492k

(Chemical Equation Presented) A convenient and efficient method to synthesize 3-(2-chloroethyl)-5-aryl-4H-pyran-4-ones 2 and 2-chloro-3-(2- chloroethyl)-1-naphthaldehydes 3 in moderate to good yields was developed via the Vilsmeier-Haack reaction of readily available 1-cyclopropyl-2-arylethanones 1 at different temperature. This reaction proceeds via sequential enolization, ring opening, haloformylation, and intramolecular nucleophilic cyclization or Friedel-Crafts alkylation reactions to produce 2 or 3.

Full text of DOI:10.1021/jo801492k

Vilsmeier-Haack Reaction of 1-Cyclopropyl-2-arylethanones
Xiang-Ying Tang and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed July 7, 2008
A convenient and efficient method to synthesize 3-(2-chloroethyl)-5-aryl-4H-pyran-4-ones 2 and 2-chloro-
3-(2-chloroethyl)-1-naphthaldehydes 3 in moderate to good yields was developed via the Vilsmeier-Haack
reaction of readily available 1-cyclopropyl-2-arylethanones 1 at different temperature. This reaction
proceeds via sequential enolization, ring opening, haloformylation, and intramolecular nucleophilic
cyclization or Friedel-Crafts alkylation reactions to produce 2 or 3.
Introduction
limitation because the weakly electrophilic Vilsmeier reagent
reacts efficiently only with electron-rich aromatic systems.2,3
Cyclopropane-containing compounds, which can be used as
versatile building blocks in organic synthesis, have been well
understood for their well-known “unsaturated” character, which
makes them readily go through a wide range of ring-opening
reactions under the influence of many electrophilic and nucleophilic
reagents. Previously, we reported SnCl4 and TMSOTf mediated
reactions of cyclopropyl alkyl ketones 1 with R-ketoesters and
allenic esters as novel methods for the synthesis of 1,6-dioxa-
spiro[4.4]non-3-en-2-ones with high stereoselectivities, as well as
dihydrofuro[2,3-h]chromen-2-one and 2,3-dihydrobenzofuran-4-
ol derivatives in moderate to good yields under mild conditions.4
As 1-cyclopropyl-2-arylethanones 1 contain a methylene group and
The halomethyleniminium salt derived from N,N-dimethyl-
formamide (DMF) and phosphoryl chloride (POCl3) is a
potential intermediate involved in the Vilsmeier-Haack reac-
tion.1 The broad synthetic utility of this halomethyleniminium
salt is not restricted to formylation but is also suitable for
electrophilic substitutions followed by intramolecular cycliza-
tions, producing various nitrogen and oxygen based hetero-
cycles.1 Among the versatile useful applications, the carbon-
carbon bond-forming reactions of the Vilsmeier reagent with
aliphatic substrates, particularly carbonyl compounds containing
a methyl or methylene group adjacent to the carbonyl group,
have been the interest of many organic chemists. Though the
Vilsmeier-Hacck reaction is widely used and will continue to
be an active and fruitful research area, there is a significant
(2) For reviews on the Vilsmeier-Haack Reaction, see: (a) Jutz, C. AdV.
Org. Chem. 1976, 9, 225. (b) Meth-Cohn, O.; Tarnowski, B. AdV. Heterocycl.
Chem. 1982, 31, 207. (c) Meth-Cohn, O.; Stanforth, S. P. In ComprehensiVe
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, p 777. (d) de Maheas, M.-R. Bull. Soc. Chim. Fr. 1962, 1989. (e)
Minkin, V. I.; Dorofeenko, G. N. Russ. Chem. ReV. 1960, 29, 599.
(3) (a) Nirmala, K. N.; Asokan, C. V. Tetrahedron Lett. 1997, 38, 8391. (b)
Thomas, A. D.; Asokan, C. V. Tetrahedron 2004, 60, 5069. (c) Arindam, C.;
Jayanta, K. R. Synth. Commun. 1995, 25, 1869. (d) Lebedev, A. V.; Lebedeva,
A. B.; Sheludyakov, V. D.; Kovaleva, E. A.; Ustinova, O. L.; Kozhevnikov,
I. B. Russ. J. Gen. Chem. 2005, 75, 412. (e) Weissenfels, M.; Pulst, M.; Cao,
W.; Riedel, D.; Greif, D. Molecules 1996, 1, 264.
(1) (a) Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119. (b)
Jutz, C. AdV. Org. Chem. 1976, 9, 225–342. (c) Seshadri, S. J. Sci. Ind. Res.
1973, 32, 128–149. (d) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–
659. (e) Marson, C. M. Tetrahedron 1992, 48, 3659–3726. (f) Meth-Cohn, O.
Heterocycles 1993, 35, 539–557. (g) Perumal, P. T. Indian J. Heterocycl. Chem.
2001, 11, 1–8. (h) Pan, W.; Dong, D.-W.; Liu, Q. Org. Lett. 2007, 9, 2421–
2423. (i) Wang, K.-W.; Xiang, D.-X.; Dong, D.-W. Org. Lett. 2008, 10, 1691–
1694.
10.1021/jo801492k CCC: $40.75
Published on Web 09/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8317–8320 8317

Tang and Shi
TABLE 1. Reaction of 1-Cyclopropyl-2-phenylethanone (1a) with
Vilsmeier Reagent under Various Reaction Conditions
SCHEME 1. Vilsmeier-Haack Reaction of 1a at 110 and
120 °C
yield (%)b
entrya
POCI3 (equiv)
t (min)
2a
3a
1
2
3
4
5
6
7
8
5
10
15
12
12
12
12
12
60
20
20
20
10
40
60
40
30
68
46
71
31
40
37
57c
d
d
11
d
d
20
25
d
TABLE 2. Summary of Temperature Effect
a All reactions were performed with la (0.3 mmol) and DMF (3 mL).
b Isolated yield. c Reaction was conducted at 80 °C. d Cannot be isolated
by flash column chromatography.
yield (%)a
entry
T (°C)
2a
3a
a cyclopropane adjacent to the carbonyl group, we envisaged that
treatment of these substrates with dehydrating reagents might lead
to interesting transformations.5 Experiments along these lines did
not look promising until we treated 1 with the Vilsmeier reagent.
As a result, we found a convenient and efficient method for the
synthesis of substituted pyranones 2 and naphthaldehydes 3,
respectively, by carrying out the Vilsmeier-Haack reaction of
readily available 1 at different temperatures. In this paper, we wish
to report our findings in this area. To the best of our knowledge,
this is the first report that these substrates, which have an electron-
withdrawing group on the benzene ring, can undergo Vilsmeier-
type reaction.
1
2
3
4
100
110
120
135
71
20
0
b
41
53
46
0
a Isolated yields. b Cannot be isolated by flash column chromato-
graphy.
(Table 1, entries 6 and 7). In addition, 2a was obtained in 57%
yield when the reaction was performed at 80 °C under otherwise
identical conditions (Table 1, entry 8). In all the cases shown in
Table 1, 3a was formed as a minor product.
Next, we attempted to obtain compound 3a as a sole product.
By raising the reaction temperature to 110 °C, both 2a and 3a
were obtained in 20% and 41% yields, respectively (Scheme
1). When the reaction of 1a with the Vilsmeier reagent (12.0
equiv) was performed at 120 °C, we found that 3a was formed
in 53% yield without the formation of 2a, suggesting that 3a
could be formed as a sole product at higher temperature (Scheme
1). The summary of the temperature effect on this reaction is
in Table 2. It is clear that the temperature can significantly affect
the reaction outcomes. The optimal temperature for the forma-
tion of 3 was 120 °C. Upon treatment of another substrate
1-cyclopropyl-2-(3-methoxyphenyl)ethanone 1k with the Vils-
meier reagent under the same conditions, compound 3k, an
analog of 3a, was obtained, and its structure was unambiguously
confirmed by the X-ray single crystal analysis, the CIF data of
which are presented in Supporting Information.6
Having these optimized reaction conditions in hand, we next
attempted to determine the reaction generality. However, we
found that upon treatment of 2-(4-chlorophenyl)-1-cyclopropy-
lethanone 1b and 1-cyclopropyl-2-(3-methoxyphenyl)ethanone
1k with the Vilsmeier reagent (12.0 equiv) at 100 and 120 °C,
to our surprise, the reaction consequences were quite different.
Using 1b as the substrate afforded 2b as a major product along
with a trace of 3b at 100 °C, but both 2b and 3b were obtained
in 24% and 41% yields at 120 °C, respectively. Using 1k as
the substrate afforded 3k as a sole product despite changing
Results and Discussion
We initially chose 1-cyclopropyl-2-phenylethanone 1a as a
model to investigate its reaction behavior upon heating with the
Vilsmeier reagent (POCl3/DMF, 5.0 equiv) under different condi-
tions. Treatment of 1a with the Vilsmeier reagent at 100 °C for
1 h afforded 3-(2-chloroethyl)-5-phenyl-4H-pyran-4-one 2a as a
yellow liquid along with trace of naphthaldehyde 3a and the
recovery of starting materials 1a in 30% within 1 h (Table 1, entry
1). To our delight, increasing the amount of the Vilsmeier reagent
to 10.0 equiv produced 2a in 68% yield along with a trace of 3a
and the complete conversion of 1a after 20 min (Table 1, entry 2).
Further investigations were aimed at determining the optimal
conditions by changing the ratio of the Vilsmeier reagent and 1a,
as well as altering the reaction time. The results of these
experiments are summarized in entries 3-8 in Table 1. As can be
seen in Table 1, in the presence of a large excess amount of the
Vilsmeier reagent (15.0 equiv), 2a was obtained in a much lower
yield of 46% along with the formation of naphthaldehyde 3a in
11% yield (Table 1, entry 3). However, using 12.0 equiv of POCl3/
DMF under identical conditions afforded 2a in 71% yield (Table
1, entry 4). Further investigation of the reaction time revealed that
increasing or decreasing the reaction time did not improve the yields
of 2a and that the optimal reaction time was 20 min (Table 1,
entries 5-7). For example, when the reaction time was prolonged
to 40 and 60 min, product 2a was obtained in 40% and 37% yields
along with the formation of 3a in 20% and 25% yields, respectively
(6) The crystal data of 3k have been deposited in CCDC with number 662441.
Empirical formula, C14H12O2Cl2; formula weight, 283.14; crystal size, 0.483 ×
0.301 × 0.190; crystal color, habit, colorless, prismatic; crystal system, triclinic;
lattice type, primitive; lattice parameters, a ) 4.4303(9) Å, b ) 10.037(2) Å, c
) 14.798(3) Å, R ) 87.946(4)°, ꢀ ) 87.265(4)°, γ ) 79.808(3)°, V ) 646.7(2)
Å3; space group, P-1; Z ) 2; Dcalc ) 1.454 g/cm3; F000 ) 292; R1 ) 0.0449,
wR2 ) 0.1207. Diffractometer: Rigaku AFC7R.
(4) (a) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709–1712. (b) Shi, M.;
Tang, X.-Y.; Yang, Y.-H. Org. Lett. 2007, 9, 4017.
(5) It was found that compound 1a decomposed after 1 h upon treatment
with DMF/(COCl)2 or PBr3/CBr4 at 100 °C.
8318 J. Org. Chem. Vol. 73, No. 21, 2008

Vilsmeier-Haack Reaction of 1-Cyclopropyl-2-arylethanones
TABLE 3. Vilsmeier-Haack Reaction of Various
1-Cyclopropyl-2-arylethanones
SCHEME 2. Vilsmeier-Haack Reaction of
1-Cyclopropyl-2-(3-methoxyphenyl)ethanone 1k at Room
Temperature
yield, 2c or
entrya
1
R
T (°C)
3 (%)b
SCHEME 3. Treatment of 2a with Vilsmeier Reagent at 120
°C
1b, p-CI
100
135
100
135
100
135
100
135
100
135
100
135
100
120
100
120
100
120
80
2b, 44
3b, 42
2c, 43
3c, 39
2d, 45
3d, 67d
2e, 65
3e, 75
2f, 51
3f, 60d
2g, 31
3g, f
2
1c, p-Br
3
1d, m-Br
1e, p-F
4
5
1f, m-F
entries 1-6). Only in the case of substrate 1g bearing an ortho Br
atom on the benzene ring, a trace of 3g was obtained, presumably
due to the electronic effect and steric hindrance (Table 3, entry
6).8 In the case of substrates 1h and 1i, the corresponding 4H-
pyranone derivatives 2h and 2i were formed in 52% and 61% yields
at 100 °C and the yield of 3h was 40%, but only a trace of 3i was
formed at 135 °C (Table 3, entries 7 and 8).8 Moreover, for
substrates 1k and 1l bearing a strongly electron-donating methoxy
group and a moderately electron-donating methyl group in the meta
position of the benzene ring, the reactions proceeded much more
smoothly to afford the corresponding 4H-pyranone derivatives 2k
and 2l in 69% and 59% yields along with traces of 3k and 3l at 80
and 100 °C, respectively (Table 3, entries 10 and 11). Moreover,
naphthaldehyde derivatives 3k and 3l were formed in moderate
yields at 120 °C as the sole products (Table 3, entries 10 and 11).
For substrates 1j and 1m, bearing a strongly electron-donating
methoxy group and a moderately electron-donating methyl group
in the ortho position of the benzene ring, the corresponding 4H-
pyranone derivatives 2j and 2m were formed in 51% and 48%
yields at 100 °C, respectively. However, the corresponding naph-
thaldehyde derivatives 3j and 3m were not formed under the
standard conditions, presumably due to the electronic effect and
steric hindrance (Table 3, entries 9 and 12).8 In the case of
1-cyclopropyl-2-naphthylethanone 1n, complex product mixtures
were formed at 100 °C, while raising the reaction temperature to
120 °C afforded the corresponding naphthaldehyde 3n in 68% yield
(Table 3, entry 13).
6
1g, o-Br
7
1h, p-Me
1i, p-MeO
1j, o-MeO
1k, m-MeO
1l, m-Me
1m, o-Me
2h, 52
3h, 40
2i, 61
3i, f
8
9
2j, 51e
3j, 0e
10
11
12
13
2k, 69
3k, 78
2l, 59
3l, 74
2m, 48e
3m, 0e
complex
3n, 88
120
100
120
100
120
100
120
1n, -C4H4-
(R-naphthyl)
a Reaction conditions: (i) POCI3/DMF (12.0 equiv); 20 min. b Isolated
yields. c Trace ot 3 was formed in most cases. d A pair of isomeric
mixtures was obtained (see Supporting Intormation). e The product 3
was not formed. f Cannot be isolated by flash column chromatography.
the temperature from 100 to 120 °C without the formation of
2k. On the basis of these results, we realized that the electron-
withdrawing group or electron-donating group on the benzene
ring of the substrates significantly affected the Vilsmeier-Haack
reaction outcomes as a result of the weak electrophilicity of
the Vilsmeier reagent. Ror substrates having electron-donating
groups on the benzene ring, the Vilsmeier-Haack reaction can
proceed much more easily under identical conditions. On the
other hand, for substrates bearing electron-withdrawing groups
on the benzene ring, higher reaction temperature is required.
Accordingly we continued to determine the scope and limitations
of these reactions. Thus, a series of 1-cyclopropyl-2-arylethanones
1b-1g having an electron-withdrawing group on the benzene ring
were subjected to the Vilsmeier reagent (12.0 equiv) at 100 and
135 °C, respectively.7 The corresponding 4H-pyranone derivatives
2b-2g were obtained in moderate yields along with traces of
3b-3g (Table 3, entries 1-6) at 100 °C, and the corresponding
naphthaldehyde derivatives 3b-3g were obtained as the sole
products in moderate yields in most cases at 135 °C (Table 3,
To gain more mechanistic insights into this interesting ring-
opening/cyclization reaction, two control experiments were con-
ducted under the standard reaction conditions. Upon treatment of
1k with the Vilsmeier reagent (POCl3/DMF, 12.0 equiv) at room
temperature for 24 h followed by quench of the reaction with the
addition of water, we found that products 2k, 3k, and 4 were
obtained in 26%, 12%, and 29% yields, respectively (Scheme 2).
In addition, no reaction occurred when 2a was subjected to the
Vilsmeier reagent (POCl3/DMF, 12.0 equiv) at 120 °C, suggesting
that naphthaldehyde derivative 3 is not derived from 4H-pyranone
derivative 2 under the reaction conditions; in other words, naph-
thaldehyde 3 is the thermodynamically more stable product and
product 4 might be the intermediate in this reaction (Scheme 3).
On the basis of above results and previous literature,3a,b
a
plausible mechanism for the formation of 2 and 3 is outlined in
(7) For these substrates having electron-withdrawing group on the benzene
ring, the Vilsmeier-Hacck reaction should be conducted at 135 °C to produce
a clean product.
(8) The reasons why none of naphthaldehyde derivatives 3j and 3m and a
trace of 3g and 3i were formed will be explained later in this paper.
J. Org. Chem. Vol. 73, No. 21, 2008 8319

Tang and Shi
SCHEME 4. Plausible Reaction Mechanism
formed due to that half of the position to form the hexatomic ring
via intramolecular Friedel-Crafts reaction is occupied by electron-
withdrawing ortho-Br atom in 1g, which does not facilitate such
electrophilic substitution either. This is also why in the reactions
of 1 bearing an electron-withdrawing group on the benzene ring
with the Vilsmeier reagent, the higher reaction temperature is
required.
In summary, a convenient and efficient method for the
synthesis of 3-(2-chloroethyl)-5-aryl-4H-pyran-4-ones 2 and
2-chloro-3-(2-chloroethyl)-1-naphthaldehydes 3 was developed
from the Vilsmeier-Haack reaction of cyclopropyl alkyl ketones
1, which involves sequential enolization, ring-opening, halo-
formylation, and intramolecular nucleophilic cyclization or
Friedel-Crafts alkylation reactions. This synthetic protocol is
associated with readily available starting materials, a structurally
wide range of products, and easy control of the reaction
conditions. The potential utilization and extension of the scope
of the methodology are currently under investigation.
Experimental Section
General Procedure for the Reaction of 2a and 3a. The
Vilsmeier reagent was prepared by adding POCl3 (4.5 mmol)
dropwise to ice-cold dry DMF (2 mL) under stirring. After 10 min,
to the above Vilsmeier reagent was added 1-cyclopropyl-2-
phenylethanone 1a (48 mg, 0.3 mmol) as a solution in DMF (1.0
mL). The reaction mixture was stirred at 100 °C (120 °C/135 °C)
for 20 min. Then the mixture was poured into ice-cold water (20
mL) and extracted with dichloromethane (3 × 20 mL), and the
combined organic phases were washed with water (3 × 20 mL),
dried over MgSO4, and filtered. The organic layer was removed
under reduced pressure, and then the residue was purified by flash
column chromatography.
3-(2-Chloroethyl)-5-phenyl-4H-pyran-4-one (2a). A yellow oil.
1H NMR (CDCl3, 300 MHz, TMS) δ 2.87 (t, J ) 6.0 Hz, 2H,
CH2), 3.81 (t, J ) 6.0 Hz, 2H, CH2), 7.38-7.46 (m, 3H, Ar),
7.50-7.53 (m, 2H, Ar), 7.80 (s, 1H), 7.91 (s, 1H); 13C NMR
(CDCl3, 75 MHz, TMS) δ 29.6, 42.6, 125.6, 128.4, 128.7, 129.0,
131.0, 152.9, 153.0, 176.6; IR (CH2Cl2) ν 3082, 2964, 2924, 1646,
1616, 1493, 1448, 1281, 1192, 1047 cm-1; MS (EI) m/z (%) 234
[M+] (12.3), 235 (7.0), 200 (15.9), 199 (100), 119 (6.8), 115 (7.3),
102 (16.0), 89 (8.8); HRMS (EI) calcd for C13H11O2Cl (M+) requires
234.0448, found 234.0457.
2-Chloro-3-(2-chloroethyl)-1-naphthaldehyde (3a). A yellow
solid. Mp 68-70 °C. 1H NMR (CDCl3, 300 MHz, TMS) δ 3.40 (t,
J ) 6.6 Hz, 2H, CH2), 3.86 (t, J ) 6.6 Hz, 2H, CH2), 7.55 (t, J )
7.2 Hz, 1H, Ar), 7.64 (td, J ) 7.2 Hz, J ) 0.9 Hz, 1H, Ar), 7.82
(d, J ) 7.8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 8.98 (d, J ) 9.0 Hz, 1H,
Ar), 10.9 (s, 1H); 13C NMR (CDCl3, 75 MHz, TMS) δ 36.7, 43.0,
124.5, 127.2, 128.0, 128.1, 129.5, 130.4, 131.8, 133.1, 136.2, 140.1,
192.9; IR (CH2Cl2) ν 3058, 2925, 2853, 1690, 1589, 1495, 1454,
1377, 1261, 1069 cm-1; MS (EI) m/z (%) 252 [M+] (20.7), 203
(42.2), 79 (100), 175 (25.3), 152 (25.9), 151 (42.9), 139 (21.4), 41
(35.8). Anal. Calcd. for C13H10Cl2O: C, 61.68; H, 3.98. Found: C,
61.41; H, 4.11.
Scheme 4 using 1a as a model. At first, 1a is easily transformed
into its enol intermediate A with hydrochloric acid produced by
the Vilsmeier reagent, which is alkylated to give a N,N-dimethy-
laminovinyl ketone B that undergoes a subsequent ring-opening
reaction by chloride ion to generate enolate C. This reactive
intermediate C further reacts with the Vilsmeier reagent to give a
biiminium salt intermediate D, which undergoes a nucleophilic
replacement by chloride ion to form intermediate E. This is the
key intermediate in this transformation. When the reaction tem-
perature is 80-100 °C, intermediate E is mainly hydrolyzed by
water to give intermediate F, which produces intermediate G
through cyclization along with the elimination of dimethylamine.
Dehydrochlorination of intermediate G furnishes 4H-pyranone
product 2a. On the other hand, when the reaction is performed at
higher temperature (120 °C or at 135 °C for other substrates),
intermediate E can generate a new hexatomic ring via an intramo-
lecular Friedel-Crafts reaction to form intermediate H. Hydrolysis
of intermediate H by water affords intermediate I, which gives
naphthaldehyde 3a after elimination of dimethylamine. It should
be also noted that intermediate E can also be partially transformed
into intermediate H when the reaction is carried out at 80 or 100
°C, affording naphthaldehyde 3a in low yield, particularly if the
reaction time is prolonged. This is why trace of 3 was obtained
along with the formation of 2 as shown in Tables 1 and 2, although
2a can not be transformed to 3a under the reaction conditions.
Now we can explain why naphthaldehydes 3j and 3m were not
formed upon treatment of 1j and 1m with the Vilsmeier reagent
under the standard conditions. According to the substituent effects,
the electron-donating group facilitates the electrophilic substitution
at the ortho and para position of the benzene ring rather than the
meta position, and thus the intramolecular Friedel-Crafts reaction
at the meta position of the o-methoxy or o-methyl group does not
take place. What is more, the steric effects of ortho substituents
are also significant since in these cases, the corresponding products
3 are not formed. For the same reason, trace of 3i is obtained
because of the p-methoxy group deactivated its meta-position and
the Friedel-Crafts reaction is difficult. Meanwhile, trace of 3g is
Acknowledgment. We thank the Shanghai Municipal Com-
mittee of Science and Technology (04JC14083, 06XD14005),
and the National Natural Science Foundation of China (20472096,
203900502, 20672127, and 20732008).
Supporting Information Available: Spectroscopic data (1H,
13C spectroscopic data), HRMS of the compounds shown in Tables
1 and 2, X-ray crystal structure of compound 3k in CIF format,
and detailed description of experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801492K
8320 J. Org. Chem. Vol. 73, No. 21, 2008