J . Org. Chem., Vol. 40, No. 21, 1975 3037
Reaction of Thionyl Chloride with Cinnamic Acids
Oxidations By Thionyl Chloride. VI. Mechanism of the Reaction with Cinnamic Acids1y2 Tatsuo Higa Department of Chemistry, University of Hawaii, Honolulu, Hawaii 96822
Arnold J. Krubsack* Department of Chemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39401 Received April 3, 1975 Thionyl chloride, in the presence of catalytic amounts of pyridine, apparently adds across the double bonds of n&unsaturated carboxylic acids to form P-chloro-a-chlorosulfinyl acid chloride intermediates which are converted to u,P-dichloro-a-chlorosulfenyl acid chlorides which can be isolated. Thus, trans-crotonic acid ( 1 1 ) gave 2chlorosulfenyl-2,3-dichlorobutanoylchloride (12,55%) which upon heating decomposed to trans- 2-chloro-2-butenoyl chloride (13) and sulfur dichloride. trans-Cinnamic acid (9) furnished 3-chloro-2-chlorocarbonylbenzo[blthiophene (4, 69%) and trans-2-chloro-3-phenylpropenoyl chloride (5, 23%) as a result of further transformation of the sulfenyl chloride 3 which could be isolated in 19% yield. Mechanism of the cyclization of 3 to 4 was studied by product analyses in the reaction with rn-nitrocinnamic acid (20), rn-methoxycinnamic acid (26), p-nitrostilbene (31), 3-(3-methoxyphenyl)propanoicacid (36), and 3-(3-formylphenyl)propanoic acid (45). Both electrophilic and nucleophilic cyclizations were rejected by successful isolation of the benzo[b]thiophenes 21 and 22 from 20 and of 27,28,29, and 30 from 26. Isolation of only benzo(b1thiophene 34 from the reaction of 31 eliminated episulfide 33 as an intermediate. Formation of 3-unchlorinated benzo[b]thiophenes 37, 38, and 39 furnished evidence for a concerted elimination-cyclization (CEC) mechanism. The reaction of 45 did not give the expected 3-unchlorinated benzo[b]thiophenes, but the benzo[b]thiophenes 50. Formation of 50 could be rationalized in terms of the stereochemical consequence of the CEC mechanism in the transition state. The CEC mechanism appeared to be the most reasonable explanation for the formation of the minor products, 22 and 51.
In the presence of a catalytic amount of a tertiary amine, thionyl chloride generally oxidizes carboxylic acids and ketones a t a carbon atoms to form a-chloro-a-chlotosulfenyl derivatives and their subsequent reaction products. Thus, 3-phenylpropanoic acid (I), for example, when treated with an excess of thionyl chloride and a small amount of pyridine, can be converted to sulfenyl chloride 2, which then undergoes further reaction to form benzo[b]thiophene 4 and a-chlorocinnamoyl chloride ( 5 ) via intermediate 3 (eq Another example is the conversion of methyl ketones to
L
J
SCl 6
0
CI
7
0 12
-2HCI
Cocl
1
SOCI,
(3)
\SOCI,
[phrH+ocl
1
C1 $=o
I
8
SCl
4
3
4
-SCI,
H
I Ph--C=C-COCI
I
c1 5
3-thietanones 7 presumably through intermediates 6, that offered a one-step synthesis of the four-membered hetereocycles (eq 2).4 The proposed mechanism3 for the formation of 2 from 1, that involved Hell-Volhard-Zelinsky type reaction of 1 with thionyl chloride to form sulfinyl chloride 8 and subsequent Pummerer-type rearrangement of 8 to 2 (eq 3), was
0
II R-C-CH,-S-CHl
0
I
0 SOCI,
II
CI
I
+
R-C-CH-S-CH, SO,
+ HCI
(4)
supported by detection3 of the sulfinyl chloride analogous to 8 from the reaction of 2-methyl-3-phenylpropanoic acid with thionyl chloride-pyridine reagent and by the thionyl chloride induced rearrangement of @-keto sulfoxides5 (eq 4), the latter being essentially the same sequence as 8 to 2. We have shown that @-chlorination$ such as the transformation of 2 to 3, is also a general reaction and that 3 but not 2 undergoes cyclization under the reaction conditions. Like its saturated analog, cinnamic acid 9 can also react with thionyl chloride to form 4 and 5 uia the sulfenyl chloride 3. In this paper we describe the mechanism of the reaction of thionyl chloride with cinnamic acids.
3038
J. Org. Chem., Vol. 40, No. 21, 1975
Higa and Krubsack
Results and Discussion Treatment of 9 with 4 equiv of thionyl chloride and 0.12 equiv of pyridine at 120-125' for 3 hr furnished 4 and 5 in 69 and 23% yield, respectively. Under milder conditions (bath temperature 8 8 O , 24 hr) sulfenyl chloride 3 could be isolated in 19% yield. Sulfenyl chloride 3, a yellow, viscous oil, showed in the infrared spectrum characteristic3,' multiple bands (5.55, 5.65, and 5.70 pm) in the carbonyl region and NMR absorption at T 2.54 (aromatic) and 4.21 (methine proton). The initial step of the reaction of thionyl chloride with cinnamic acid is no doubt an electrophilic addition of thionyl chloride across the double bond of cinnamoyl chloride to form sulfinyl chloride 10 which is then converted to 3 by the Pummerer reaction (eq 5). Such additions of H
r
I
Ph -C=C-C02
I H
H
,C1
A
d.1 3
-9
Ph-CB-CHCOC1
10
9
thionyl chloride to carbon-carbon multiple bonds have been reported for at least three different types of compounds: enol ethers,s l,l-diarylethylene~,~ and acetylenedicarboxylic acid.1° The addition is particularly facile in the former two types of compounds; for example, the addition to an enol ether to form a sulfoxide is effected at OB in the absence of catalyst. In contrast to such electron-rich double bonds, the double bonds of a,P-unsaturated carboxylic acids such as 9 do not allow the addition of thionyl chloride in the absence of a catalyst. trans-Crotonic acid ( l l ) , for example, when treated with an excess of thionyl chloride at reflux for 48 hr, gave no addition products but only crotonyl chloride, while the treatment of 11 with 7 equiv of thionyl chloride and 0.12 equiv of pyridine'l at moderate reflux for 3 hr afforded a mixture which showed virtually no trace of either 11 or crotonyl chloride, as revealed by NMR spectroscopy. Fractional distillation of the mixture furnished sulfenyl chloride 12 and 2-chloro-2-butenoyl chloride (13) in 55 and 10% yield, respectively. The latter was identified by converting it to the known13 trans- 2-chloro-2-butenamide. Sulfenyl chloride 12, an approximately 1:l mixture of diastereomers, revealed infrared absorption at 5.56 and 5.67 pm and NMR signals at 7 5.10 (9, 1 H, J = 6.5 Hz), 8.20 and 8.27 (two sets of d, 3 H, J = 6.5 Hz). Sulfenyl chloride 12 apparently eliminates sulfur dichloride when treated with pyridine hydrochloride and thionyl chloride at reflux, furnishing 13.
e1
e1
H
I
CH,--C=C-C02H
-+
I
CH,-CH-C-COCl
I
-
I
I
I
16
tI
mechanisms: (a) direct electrophilic substitution; (b) electrophilic substitution of the intermediate 14 which could be formed by 1,2 elimination of hydrogen chloride; (c) rearrangement of 14 to episulfide 15 which could then be transformed into 4 by either nucleophilic attack by sulfur or by a concerted process via 16; (d) concerted transformation of 14 which can be regarded as a 6-n-electron system; (e) concerted elimination-cyclization of 3 via 16 (see Scheme I). We evaluated each of those mechanisms by means of product analyses and abandoned all but path e. Electrophilic Cyclization. Treatment of sulfenyl chloride 2 with pyridine hydrochloride under the conditions in which 3 underwent cyclization gave only intractable tar. The anticipated benzo[b]thiophene-2-carbonyl chloride could not be is01ated.l~Furthermore, 3,3-diphenylpropanoic acid (17a), when treated with thionyl chloride and pyridine, furnished benzo[b]thiophene 19a in 65% yield; however 3-phenylbutanoic acid (17b) produced 19b in 16% yield15 even though 17b is converted completely to sulfenyl chloride 18b under the conditions. Thus, sulfenyl chlorides
-%I*
17
SCl
H 11
Scheme I
I
sc1 18
12
R
H I I CH3-C4-COCI
I
(7)
(6)
Cl 13
Treatment of 3 with a catalytic amount of pyridine hydrochloride at 130' for 5 hr afforded a mixture of 3 (32%), 4 (38%), and 5 (30%) as revealed by NMR spectroscopy. Fractional crystallization of the mixture from carbon tetrachloride afforded benzo[b]thiophene 4 in 36% yield. To account for the cyclization of 3 to 4 we proposed five possible
COCl 19
a,R=Ph b, R = Me 3 and 18a undergo smooth cyclization, while 2 and 18b are difficult to cyclize. Comparison of these two groups of sulfenyl chlorides suggested that a direct electrophilic substitution reaction (path a) was unlikely, and that the success of ring closure seemed to be related to the acidity of the
J . Org. Chem., Val. 40, No. 21, 1975 3039
Reaction of 'rhionyl Chloride with Cinnamic Acids benzylic hydrogens of the sulfenyl chlorides. Therefore the ring closure may be related to the ease of hydrogen chloride elimination from 3 to form 14. We next examined the reaction of m-nitrocinnamic acid (20). Acid 20 was treated with 3.5 equiv of thionyl chloride and 0.12 equiv of pyridine a t 135' for 1.5 hr. The product mixture was treated with methanol and separated on an alumina column to furnish four benzo[b]thiophenes, 21a, 21b (23.4%), 22a (1.2%), and 22b (1.8%).Although 21a was
21
22 a, X = NO2; Y = H
b, X = H; Y = NO2
a major product, only a small amount of it was isolated owing to its difficult separation from 21b. The structures of those products were assigned by spectroscopic data and elemental analyses. The benzo[b]thiophenes 21 were distinguished by NMR spectroscopy,16 i.e., splitting patterns of the aromatic protons. Both minor products, 22, showed no carbonyl absorptions in their infrared spectra. Their mass spectra showed molecular ions of mle 247 (base), 249 (6870%), and 251 (14.5%), indicating the presence of two chlorine atoms. The positions of the nitro groups in 22a and 22b were assigned by correlating their ir absorption patterns in the 5-6-pm regionl7 with those of 3-chloro-&nitrobenzo[b]thiophene15 (for 22a) and 3-chloro-7-nitrobenzo[blthiophene (for 22b), prepared by saponification and decarboxylation of 21b. Since a rn-nitro group deactivates an aromatic ring to electrophilic substitution, the ease of benzo[b]thiophene formation from 20 indicated that the ring closure involved neither path a from 23a nor path b from 24a, but it rather suggested a nucleophilic process of episulfide 25a, path c (see Scheme I).
c1
C1
c1
x
X 24
23
c1
c1
x 25 a, X = NO, b, X = OCHj
Episulfide Mechanism. In view of a number of reported instances18 for rearrangement (and related transformations) of a-halo episulfides to benzo[b]thiophenes the episulfide mechanism (path c) was particularly attractive. The behavior of 20 appeared to be consistent with this mechanism. We tested this mechanism by the reactions of thionyl chloride with m-methoxycinnamic acid (26) and with p nitrostilbene (31). The reaction of 26 afforded four benzo[b]thiophenes, 27-30, under two sets of conditions. In the first set 26 was
Z I
-7
WC1 COLMe
27a, X = OMe; Y = C1; Z = H 27b, X = Y = C1; Z = H 28, X = OMe; Y = Z = C1 29, X = OMe; Y = H; Z = C1
I
OMe 30
treated with 3.5 equiv of thionyl chloride and 0.12 equiv of pyridine at 140° for 70 min, and the product mixture was treated with methanol and chromatographed on an alumina column to furnish 27a (26.4%),28 (1.4%),and 29 (0.8%). In the second set 26 was allowed to react with 7 equiv of thionyl chloride and 0.12 equiv of pyridine a t reflux (bath temperature 105O) for 48 hr to yield, after esterification with methanol and separation in the same manner, 27a (54.4%),28 (6%), and 30 (2%). Thirdly 26 was treated with an excess of thionyl chloride and a catalytic amount of pyridine a t reflux (bath temperature 95-98") for 21 hr, similar conditions that permitted isolation of sulfenyl chloride 3. Recrystallization of the product mixture from hexane furnished 27b in 41.5% yield. The acid chloride of 26 was recovered in 41.3% yield by distillation of the mother liquor. The structures of benzo[b]thiophenes 27-30 were determined by elemental and spectroscopic analyses. The mass spectra of all the compounds showed molecular ions as the base peaks and fragment ions corresponding to the loss of CH3, OCHs, COCH3, C02CH3, and CH3 CO2CH3. Each of the peaks was accompanied by isotope peaks of appropriate intensities due to 37Cland 34S.NMR spectral6 easily distinguished 27a from 30. Compound 28 was also obtained by independent treatment of 27b with thionyl chloride followed by methanolysis. In the NMR spectrum of 29, the long-range coupling16 between the CB-Hand C7-H aromatic protons permitted the assignment of the structure. These results with 26 revealed that sulfenyl chloride 23b undergoes ring closure more readily than sulfenyl chloride 3. Thus, a m-methoxy group, which should effectively suppress a nucleophilic substitution reaction, instead promotes the thiophene ring formation. Furthermore, the formation of 29 cannot be explained by a path involving episulfide 25b as an intermediate. Therefore, neither a nucleophilic nor a concerted process through an episulfide was a likely mechanism for benzo[b]thiophene formation. Further evidence against the episulfide mechanism was provided by the reaction of p-nitrostilbene (31). With its strongly electron-withdrawing group at one end of the double bond, 31 is expected to react with thionyl chloride in the same fashionlg as cinnamic acids. Thus, 31 was treated with an excess of thionyl chloride and a catalytic amount of pyridine a t reflux for 48 hr. The product mixture was chromatographed on an alumina column, affording benzo[blthiophene 34 (15.2%), a small amount of 31, and two other compounds, mp 204-205 and 208-210°, which appeared to be isomeric as shown by their nearly identical infrared spectra. One (mp 204-205') of the isomers showed a molecular ion at mle 514, which corresponds to formula CzsH1gClN204S, a dimeric structure of stilbene 31 linked by sulfur and bearing a chlorine atom. Such products presumably result by addition of sulfenyl chloride 32 to 31 and subsequent elimination of 2 mol of hydrogen chloride. We have not yet determined the structures of these products. The structure of 34 was determined by elemental and spectroscopic analyses, Le., the mass spectrum revealed molecular ions a t mle 289 and 291 and the base peak a t mle 208 [M - (NO2 + Cl)]; the NMR spectrum showed an AA'BB' pattern a t T 1.60 and 1.94 (J = 9.0 Hz) for protons ortho
+
3040
J,Org. Chem., Vol. 40, No. 21, 1975
Higa and Krubsack
Scheme I1
Scheme I11 CH,CH,CO,H --f
36
c1
c1
35
t
c1
\
LC1
c1
r
w
and meta to the nitro group, and a complex a t 7 1.91-2.52 which was closely analogous to the spectra of other 2,3-disubstituted benzo[b]thiophenes, e.g., 3-chloro-2-methoxycarbonylbenzo[b]thiophene.Thus the spectrum unambiguously distinguished 34 from its isomer 35. Should espisulfide 33 be involved in the process, there is anticipated the formation of an equal amount of 35 which we did not observe (see Scheme 11). We therefore conclude that episulfides are not intermediates in the ring closure of sulfenyl chlorides to form benzo[b]thiophenes. Concerted Mechanisms. The concerted cyclization (path d in Scheme I) should be a thermally allowed process, for intermediate 14 can be regarded as a 6-7r-electron system. The crucial step in this process appears to be 1,2 elimination of hydrogen chloride from 3 to form 14. In the concerted elimination-cyclization mechanism (CEC, path e in Scheme I), loss of hydrogen from the benzylic carbon and chlorine atom from the sulfur simultaneously closes the ring to form 16 which then expels another molecule of hydrogen chloride by a l,$-elimination process to give rise to 4. For both mechanisms acidity of the benzylic hydrogen is important to the success of the cyclization, as discussed earlier.2 We examined the operation of these mechanisms by the following reactions. Treatment of 3-(3-methoxyphenyl)propanoicacid (36) with 3.3 equiv of thionyl chloride and a catalytic amount of pyridine a t 135' for 2 hr afforded, after esterification with methanol and separation on an alumina column, the known16b benzo[b]thiophene 37 in 15.5% yield. When 36 reacted with 6.7 equiv of thionyl chloride in the presence of
c1
Cl
38
OCH,, 39
i
r
1
L
NO,
34
37
+
J
29, 37, 38
1
J
39
a small amount of pyridine at reflux for 46 hr, it furnished, after similar treatment, benzo[b]thiophenes 29, 38, and 39 in 56, 1.3, and 3% yield, respectively. The structures of the minor products 38 and 39 were determined by elemental and spectroscopic analyses. NMR spectra of both compounds revealed two singlets in the aromatic region, which indicated that one proton was a t the C3 and the other a t either Cq, Cg, or CS but not at the C7 position.16 The spectrum of 38 was compared to that of 29, while 39 was compared to 30 to establish their structures as indicated. As shown earlier in the formation of 28, the chlorine substituents in 29, 38, and 39 are results of further reaction of thionyl chloride on the methoxybenzo[b]thiophenes formed. The positions of the chlorine substituents in these compounds are coincident with activated positions under the attack of electrophilic reagents (e.g., thionyl chloride). None of the benzo[b]thiophenes here has chlorine substituents a t the C3 position. This indicates that sulfenyl chloride 40 undergoes rapid ring closure prior to transformation into 23b by P-chlorination, while the analogous sulfenyl chloride 2 undergoes cyclization only after its 6-chlorination. Apparently the success of ring closure in 40 is assisted by donation of a pair of electrons on the methoxy oxygen (see Scheme 111).Although the process can technically be regarded as an electrophilic aromatic substitution reaction, the result also suggests that the cyclization of sulfenyl chlorides such as 3 (in which a lone pair of electrons is not available) proceeds through the generation of a pair of electrons upon loss of an acidic hydrogen (Le., CEC mechanism). A possible route for the formation of 29 from the reaction of 26 then might be as follows. Sulfenyl chloride 23b undergoes cyclization to form intermediate 41 which, by loss of hydrogen chloride, would furnish the major product 27b. A fraction of 41, however, might eliminate chlorine molecule to form 44 via cation 42 or 43. The intermediate 44 would then be chlorinated by thionyl chloride a t the Cq position and esterified in the next step to furnish 29 (see Scheme IV). For further evidence of the CEC mechanism, we investigated the reaction of 3-(3-formylphenyl)propanoic acid (45) with thionyl chloride in the presence of pyridine. Since benzaldehyde is known20 to form benzal chloride when treated with thionyl chloride, 45 would first be converted to 46 and then to sulfenyl chloride 47. The hydrogen of the
J.Org. Chem., Vol. 40, No. 21, 1975 3041
Reaction of T'hionyl Chloride with Cinnamic Acids Scheme IV
23b
27b
41
42
pi-
-CI+
xacl H
CHjO
CHjO
-a+-
+
COCl
43
44
dichloromethyl group of 47 would be at least equally or more acidic than the benzylic hydrogen of 3. Thus we expected that 47 would cyclize prior to its conversion to 48 and would furnish benzo[b]thiophenes (49) which bear no chlorine atoms at their C3 positions. We treated 4521 with 4 equiv of thionyl chloride and a catalytic amount of pyridine at 140° for 105 min. The reaction mixture was then treated with methanol and separated by column chromatography, furnishing benzo[b]thiophenes 50a and 50b in 8 and 15% yield, respectively. The rest of the material was a mixture consisting mainly of the methyl ester of 46. Both 50a and 50b showed molecular ions at mle 308 which were accompanied by M 2 (equal intensity) and M 4 (ca. 35% of M+) peaks, indicating the presence of three chlorine atoms. The two benzo[b]thiophenes were easily differentiated by their NMR spectra (see Experi-
+
+
Scheme V
46
\ /
/
H
I-.
mental Section). The structural assignments, particularly the chlorine substituents at the C3 positions, were confirmed by isolating the same products, 50a (13.5%) and 50b (32.3%),from the reaction of m-formylcinnamic acid. The result reveals that sulfenyl chloride 47 undergoes ring closure only after its conversion into 48. This is in accord with the concerted cyclization mechanism through a 6-r-electron system such as 14 (path d in Scheme I). Another interpretation which is in line with the CEC mechanism is that the ring closure of 47 is sterically prohibited. The transition state of this cyclization requires two chlorine atoms of the dichloromethyl group to approach from the bottom (or top) of the phenyl ring to the plane of the ring as the hydrogen is leaving from the top (or bottom) of the plane. This process also results in the shortening of the bond lengths of one carbon-carbon and two carbon-chlorine bonds (so as to form Cl&=C). The cyclization of 47 to this intermediate by a CEC mechanism would be in a direction that creates two sites of new nonbonded interactions among the two large chlorine and two perihedral hydrogen atoms.22 Thus the process would be slower than the conversion of 47 into 48. Additional evidence for the CEC mechanism comes from the rationale for the formation of minor products, 2,3-dichlorobenzo[b]thiophenes,e.g., 22. In addition to 22, we obtained similar products 51a (1.6%) and 51b (0.7%) from the
51a, X = H b. X = OCHj
reactions of thionyl chloride with 9 and with p-methoxycinnamic acid,l5 respectively. The formation of these products can best be rationalized in terms of the stereochemical consequence of the CEC mechanism. The ring closure of 3, which is presumably a mixture of diastereomers,2* by the CEC mechanism should give rise to the diastereomeric intermediates 16a and 16b. If cis 1,4 elimination is much faster25 than trans, the elimination of hydrogen chloride from 16a could afford exclusively the major product 4. On the other hand, if the loss of hydrogen chloride from 16b is an unfavorable trans 1,4 elimination, a part of 16b might lead to the cleavage of the chlorocarbonyl group by cis 1,4 elimination to form the observed minor product (see Scheme VI). A higher yield (10%) of 51b from the reaction of methyl cinnamate provides further evidence for the proposed mechanism.26 Scheme VI
C1
elimination
L'Cl
4.5
47
H
TT
-HCI/
3 -Ha\
trans .'-mination ehmination
wz H
cis-HCI elimination, -CO
51a
COCl 16b
Experimental Section
48
Thionyl chloride (Matheson Coleman and Bell) was distilled ~~ the fracfrom triphenyl phosphite by a r e ~ o m m e n d e dprocedure; tion boiling over the range 75.5-76.5'' was used. Alumina used for chromatographic columns was Woelm neutral unless otherwise
3042 J . Org. Chem., Vol. 40, No. 21, 1975 specified. Infrared spectra were recorded with a Perkin-Elmer Model 137 spectrophotometer with a sodium chloride prism; solid samples were taken as potassium bromide pellets and liquid samples were taken as neat films. Mass spectra were processed by Mi-. C. R. Weissenberger with an AE1 MS-9 mass spectrometerz8 a t 70 eV. The nuclear magnetic resonance spectra were taken on a Varian Model A-60 spectrometer, using tetramethylsilane as the internal reference and carbon tetrachloride as solvent unless otherwise specified. Melting points were taken on a Thomas-Hoover capillary melting point apparatus and are corrected. Boiling points are uncorrected. Elemental analyses were performed by Chemalytics, Inc., Tempe, Ariz.; Crobaugh Laboratories, Cleveland, Ohio; and Galbraith Laboratories, Knoxville, Tenn. Reaction of Thionyl Chloride with trans-Cinnamic Acid (9). A. To a mixture of 9 (7.41 g, 0.05 mol) and 0.5 ml (0.006 mol) of pyridine was added approximately '14 of 24 g (0.2 mol) of thionyl chloride. The mixture was heated to 120-125' (bath 130-140'), and the rest of the thionyl chloride was added dropwise over a period of 2 hr. The mixture was stirred a t this temperature for an additional 1 hr, cooled, and dissolved in 300 ml of hexane. The solution was decanted from pyridine hydrochloride and from it was crystallized 3.85 g of the benzo[b]thiophene 4,mp 113.5-115' (lit.3 mp 114.4-115.1"). Four more crystallizations from the mother liquor gave a total of 4.14 g of 4,mp 111-114.5'; total yield of 4 was 7.99 g (69%). The liquid product was distilled to yield 2.32 g (23%) of the acid chloride 5,bp 83-92' (0.18 mm). The infrared spectrum of this product was identical with that of an authentic sample. B. A mixture of 14.82 g (0.1 mol) of 9,2 ml of pyridine, and 84 g (0.7 mol) of thionyl chloride was heated a t 65-80' (bath temperature) for 24 hr. The infrared spectrum of the sample showed that it was nearly identical with a spectrum of an authentic sample of cinnamoyl chloride. The mixture was then heated at 88' for 24 hr. After removing excess thionyl chloride by rotary evaporation the product was dissolved in 100 ml of hexane, and the mixture was filtered to remove pyridine hydrochloride. The solution was concentrated and fractionally distilled to yield 7.4 g of cinnamoyl chloride, bp 77-90' (0.2 mm); 0.8 g of an intermediate fraction, bp 100-110' (0.12 mm); and 5.8 g (19%) of sulfenyl chloride 3, bp 110-112' (0.12 mm). Redistillation of the latter compound furnished 96% pure (by NMR) 3: bp 107' (0.08 mm); ir 5.55, 5.67, 5.70, 6.88, 9.44, 9.70, 9.92, 13.25, and 14.35 pm; NMR 7 2.54 (m, 5 H) and 4.21 (9, 1 H); mass spectrum m/e 234, 232, 230, 197, 195, 169, 167, 134, 132, 125, 123 (seemingly 4); and 204, 202, 200, 167, 165, 139, 137, 102, and 101 (seemingly 5). Anal. Calcd for CgHsC140S: C, 35.56; H, 1.99; C1, 46.65; S,10.55. Found: C,36.43; H, 2.08; C1,46.39; S, 10.39. Reaction of Thionyl Chloride with trans-Crotonic Acid (11).A. To a mixture of 4.30 g (0.05 mol) of 11 (mp 71-72') and 0.5 ml (0.006 mol) of pyridine was added 42 g (0.35 mol) of thionyl chloride, The mixture was heated a t reflux (bath temperature 95') for 3 hr. Excess thionyl chloride was removed under vacuum (25 mm) in a Dry Ice-2-propanol trap. The NMR spectrum of the product mixture showed the compounds 12 and 13 in 88 and 12% yield, respectively. The mixture was dissolved in dry ether, pyridine hydrochloride was filtered, ether was removed, and the residue was distilled to yield 0.70 g (10%) of a-chlorocrotonyl chloride [bp 23-30' (0.25 mm); ir 5.70, 6.17, 8.66, 9.27, and 13.20 pm; NMR (neat) T 2.30 (9, 1 H , J = 7 Hz) and 7.88 (d, 3 H, J = 7 Hz)] and 6.66 g (55%) of sulfenyl chloride 12, bp 55-61' (0.18 mm). Redistillation of the latter compound gave a fraction with bp 46-48' (0.7 mm): ir 5.56, 5.67, 6.92, 7.22, 9.00, 9.06, 9.46, 9.76, 10.05, 12.15, 12.92, 13.40, 13.97, 14.55, and 14.86 pm; NMR T 5.10 (9, 1 H, J = 6.5 Hz) and 8.20 and 8.27 (two sets of doublets, 3 H, J = 6.5 Hz). An analytical sample, bp 56-56.5' (0.45 mm), was obtained by four more fractionations. Anal. Calcd for CdH4C140S: C, 19.86; H, 1.66; C1, 58.61; S,13.25. Found: C,20.55; H, 1.83; C1, 58.59; S,13.60. B.A mixture of 4.30 g (0.05 mol) of 1 1 and 42 g (0.35 mol) of thionyl chloride was heated a t reflux for 48 hr. Infrared and NMR spectra were recorded after 1, 19, and 48 hr. These spectra showed no change over the reaction period, and the product was identified as trans-crotonyl chloride: ir 5.72, 6.18, 7.01, 8.83, 9.24, 9.60, 10.45, and 13.13 pm; NMR (SOC12) 7 2.79 (quadrupled doublet, 1 H, J = 15.5, 7 Hz), 3.96 (quadrupled doublet, 1 H, J = 15.5, 1.6 Hz), and 8.05 (quadrupled doublet, 3 H, J = 7,1.6 Hz). 2-Chloro-2-butenoyl Amide. Acid chloride 13 (300 mg, 0.002 mol) was added dropwise to 4 ml of concentrated ammonium hydroxide solution The product was extracted with ether ( 2 X 25 ml), dried, and evaporated to yield 150 mg of a yellow solid. The solid was recrystallized from ligroin to give white, fine needles, mp
Higa and Krubsack 107-112', which were again recrystallized from water to give white prisms, mp 112-113.5' mp 112'). Decomposition of 2,3-Dichloro-2-chlorosulfenyl-3-phenylpropanoyl Chloride (3). Pyridine hydrochloride was prepared by adding several drops of thionyl chloride to a mixture of 0.04 ml of pyridine and 2 drops of methanol and removing excess thionyl chloride under vacuum. Sulfenyl chloride 3 (1.36 g, 0.0044 mol) was added to the pyridine hydrochloride and heated a t 130' for 5 hr. The reaction mixture which solidified on cooling was taken up in dry carbon tetrachloride (4 ml). The NMR spectrum of this solution showed a singlet a t T 1.85 due to 5,a complex in the aromatic region (7 1.95-2.73), and a singlet a t 7 4.33 due to 3. The ratio of these peaks gave relative yields of the compounds 3,4, and 5 a t 32, 38, and 30%, respectively. Furthermore, crystallization from the carbon tetrachloride solution afforded 380 mg (36%) of 4, mp 114-115O.
Reaction of Thionyl Chloride with m-Nitrocinnamic Acid (20). To a mixture of 3.86 g (0.02 mol) of 20 and 0.2 ml of pyridine was added at 135' over a period of 1 hr, 8.4 g (0.07 mol) of thionyl chloride. The mixture was heated a t the same temperature for an additional 30 min, cooled, and added to 75 ml of absolute methanol. The mixture was heated a t reflux for 30 min, excess methanol was removed, and the residue was chromatographed on alumina (activity grade 111, 150 9). The column was eluted with benzene into 20 fractions: 50 ml each for fractions 1-3, 100 ml each for 4-7, and 200 ml each for 8-20. Fractions 1-2 gave 0.11 g of a mixture of 22a and 22b. Each of the fractions 3-9 (2.94 g) was a mixture of 21a and 21b. Fractions 10-20 (0.99 g) were of a single component which recrystallized from ethanol and ethyl acetate to furnish 0.80 g of 21b, mp 194-196'. More 21b (0.47 g) was obtained by fractional crystallization of fractions 5-9; total yield of 21b was 1.27 g(23.4%). One more recrystallization from the same solvents afforded an analytical sample of 21b as yellow needles: mp 196.5197O; NMR (CDC13) ca. 7 1.45 (dd, H6, J = 8.0, 1.5 Hz), 1.68 (dd, H4, J = 8.0, 1.5 Hz), 2.33 (t, H5, J = 8.0 Hz), and 5.99 (s, OCH3); ir 5.76, 6.56, 7.58, and 8.02 pm; mass spectrum m/e 273, 271 (M+), 241 (-NO), 242, 240 (base, -OCH3), 196, 194 (-NOz, -OCH3), and 166 (-NOz, -COzCH3). Anal. Calcd for CloH&lN0&3: C, 44.21; H , 2.23; C1, 13.05; N, 5.16; S, 11.80. Found: C, 44.31; H, 2.14; C1, 13.36; N, 4 87; S, 12.09. Further chromatography of a mixture (1.21 g) of 21a and 21b (fractions 5-7) was attempted on activity grade I11 alumina (50 g) with benzene-petroleum ether (1:2). All fractions (11 X 50 ml) still showed two carbonyl absorptions, indicating no separation of 21a and 21b. Fractional crystallization of these fractions from ethyl acetate furnished, besides 0.105 g of 21b, 5 mg of 21a: mp 186-190'; ir 5.89, 6.60, 7.41, and 7.74 pm; mass spectrum m/e 273, 271 (base, M'), 241 (-NO), 242,240 (-OCH3), 210 (-NO, -OCH3), 196, 194 (-NOz, -OCH3), and 166 (-NOz, -COzCH3). Compound 21a (5.89) was unambigously distinguished from 21b (5.76 pm) by the carbonyl absorption. Separation of 22a and 22b was achieved on an activity grade I alumina (107 g) column by eluting with petroleum ether into five (200 ml each) fractions and petroleum ether-ether (1O:l) into 15 fractions (200 ml each). Fraction 7 afforded 50 mg of 22b, recrystallization of which from ligroin gave yellow flakes: mp 140-141'; ir 6.56, 6.64, 7.47, 7.60, 10.19, and 13.56 pm; mass spectrum m/e 251 (M 4, 14.3%), 249 (M 2, 70%), 247 (M+, loo%), 219, 217 (-NO), 203, 201 (-Nos), 168 and 166 (-NOz, -C1). Fraction 8 (34 mg) was recrystallized from ligroin to yield 22a as pale yellow flakes: mp 182-183.5'; ir 6.66, 7.45, 7.54, and 13.49 pm; mass spectrum m/e 251 (M 4, 14.5%), 249 (M 2, 68.5%), 247 (M+, loo%), 219, 217 (-NO), 203, 201 (-NOz), 168 and 166 (-NOn, -C1). 3-Chloro-7-nitrobenzo[ blthiophene. The ester 22b (1.086 g, 4 mmol) was saponified by heating it a t reflux with 50 ml of 1 N sodium hydroxide and 100 ml of ethanol for l hr. After most of the ethanol was removed the aqueous solution was acidified with 60 ml of 1 N hydrochloric acid. The precipitate was filtered to furnish 950 mg (92%) of carboxylic acid as a yellow powder, m p 309-310' dec. The acid (873 mg, 3.4 mmol) was decarboxylated by treatmentz9 with copper chromite (100 mg) and quinoline (5 ml) to yield 700 mg (98%) of crude product, treatment of which with charcoal and recrystallization from ethanol gave 530 mg of 3-chloro-7-nitrobenzo[b]thiophene as yellow needles: mp 146-147.5'; ir 6.64, 7.46, 7.62, 9.82, and 13.55 pm; NMR (CDC13) ca. T 1.59 (dd, Hfi,J = 8.0, 1.5 Hz), 1.87 (dd, H4, J = 8.0, 1.5 Hz), 2.42 (t, H5, J = 8.0 Hz), and 2.51 (s, H2); mass spectrum m/e 215, 213 (M+, base), 185, 183
+
+
+
+
Reaction of T'hionyl Chloride with Cinnamic Acids (-NO), 169,167 (-NOz), 157,155 (-NO, -CO), 132 (-NOz, -Cl), 125, and 123 (-.NOz, -CS). Reaction of Thionyl Chloride with m-Methoxycinnamic Acid (26). A. To a mixture of 3.56 g (0.02 mol) of 26 (mp 118119') and 0.2 in1 of pyridine was added approximately % of 8.4 g (0.07 mol) of thionyl chloride. The mixture was heated to 140', and the rest of the thionyl chloride was added a t a rate such as not to drop the temperature below 135' (40 min). The mixture was then heated ai, 140-145' for an additional 30 min, dissolved in benzene (30 ml), poured into a flask containing 30 ml of absolute methanol, and heated a t reflux for 30 min. After benzene and excess methanol were removed, the mixture was chromatographed on alumina (activity grade 11,100 9). The column was eluted with petroleum ether-benzene (1:l) to furnish 17 fractions (50 ml each). Recrystallization of fractions 3-6 (total 2.865 g) from methanol afforded 1.355 g (26.4%) of 27a. mp 115-116'. One more recrystallization from the same solvent furnished an analytical sample: mp 116'; ir 5.79 (C===O),6.63, and 8.14 and 8.25 pm (C-0); NMR (CDC13) ca. T 2.47 (dd, H7, J = 8.5, 0.7 Hz), 2.81 (dd, H4, J = 2.5, 0.7 Hz), 2.95 (dd, H6, J = 8.5, 2.5 Hz), and 6.09 and 6.14 (2 s, 2 OCH3); mass spectrum mle 258, 256 (M+, base), 241 (-CH3), 227, 225 (-OCH3), 197 (-COzCH3), 182 (-CH3, -C02CH3), and 119 (C7H3S). Anal. Calcd for CllH9C103S: C, 51.47; H, 3.53; C1, 13.81; S, 12.49. Found: C, 51.47; H, 3.34; C1,14.00; S, 12.30. Recrystallization of fractions 7-15 from methanol afforded 86 mg (1.4%) of 28, mp 160-172". Further recrystallization from the same solvent gave rise to 28 as pale yellow needles: mp 172.0172.8'; ir 5.79 (C=O), 6.68, 7.78,8.06, and 8.16 and 8.22 pm (C-0); NMR (CDC13) 7 2.36 (d, H7, J = 8.5 Hz), 2.78 (d, H6, J = 8.5 Hz), and 6.04 (s, 2 OCH3); mass spectrum mle 294, 292,290 (M+, base), 277, 275, (-CH3), 261,259 (-OCH3), 249, 247 (-CO, -CH3), 233, 231 (-C02CH3), 218, and 216 (-CH3, -CO2CH3). Anal. Calcd for C11HeC1203S: C, 45.38; H, 2.77; C1, 24.35; S, 11.01. Found: C, 45.44; H, 2.36; C1, 24.38; S, 10.98. The residues (1.60 g) after crystallization of 27a and 28 were combined and chromatographed again on alumina (activity grade 111, 40 g) with petroleum ether (13 fractions, 50 ml each) and benzene (one fraction, 200 ml). Each of the fractions 1-13 was still a mixture. Two recrystallizations of fraction 14 (160 mg) from methanol afforded 40 mg of 29 as white needles: mp 159-160"; ir 5.82 (C=O), 6.57, and 8.03 pm (C-0); NMR ((2DC13) T 1.85 (d, H3, J = 0.7 Hz), 2.32 (dd, H7, J = 8.5, 0.75 Hz), 2.82 (d, H6, J = 8.5 Hz), and 6.03 (s, 2 OCHs); mass spectrum mle 258, 256 (M+, base), 243, 241 (-CH3), 227, 225 (-OCH3), 215, 213 (-CH3, -CO), 199, 197 (-COzCH3), 184, and 182 (-CH3, -COzCH3). B. A mixture of 7.12 g (0.04 mol) of 26, 0.4 ml of pyridine, and 33.6 g (0.28 mole) of thionyl chloride was heated at reflux for 21 hr. The oil bath temperature was kept a t 95-98'. After excess thionyl chloride was removed, the reaction mixture was taken up in 500 ml of dry hexane, heated to ensure dissolution, and decanted from pyridine hydrochloride. Two crystallizations from the solution furnished 4.34 g (41.5%) of acid chloride 2 7 b mp 147.3-148.3'; ir 5.66 (C=O), 6.73,8.18 (C-0), and 8.57 rm. Further crystallization from the mother liquor gave 0.93 g of a mixture of solids, mp 117-128". Treatment of 27b with methanol in ether gave 27a. mp 116'. The red liquid left after separation of the solids was distilled to yield 3.25 g (41.3%) of m-methoxycinnamoyl chloride, bp 107-112' (0.26 mm), and a small amount of residue. The acid chloride (1.90 g) was hydrolyzed with aqueous acetone to afford 1.45 g of acid 26, mp 117-119'; mixture melting point with an authentic sample of 26 showed no depression, and the infrared spectra were identical. C. A mixture of 2.67 g (0.015 mol) of 26,0.15 ml of pyridine, and 12.0 g (0.1 mol) of thionyl chloride was heated a t reflux (bath temperature 105') for 48 hr. The product mixture, which solidified upon cooling, was dissolved in 70 ml of benzene and 20 ml of absolute methanol and heated a t reflux for 1 hr. After benzene and excess methanol were removed, the residue was separated on an alumina (activity grade 111, 150 g) column by eluting with petroleum ether-benzene 10:3) (33 fractions of 50 ml each). Recrystallization of fraction 7 (145 mg) from methanol afforded 75 mg (2%) of the benzo[b]thiophene 30 as white, fine needles: ir 5.80 (C=O), 6.68, 7.64, 7.89, and 8.60 pm; NMR ca. 7 2.49 (dd, H4, J = 7.7, 1.7 Hzi, 2.67 (t, H5, J = 7.9 Hz), 3.18 (dd, H6, J = 7.0, 1.7 Hz), and 6.00 and 6.05 (2 s, 2 OCH3); mass spectrum mle 258, 256 (H+, base), 243, 241 (-CH3), 227, 225 (-OCH3), 215, 213 (-CH3, -cO), 197 (-COzCH3), 184, 182 (-C02CH3, -CH3), and 119 (C7H3S+); mol wt (mass spectrum) for CllH9C103S 255.99572 (calcd, 255.99609).
J . Org. Chem., Vol. 40, No. 21, 1975 3043 Recrystallization of fractions 9-16 (total 2.75 g) from methanol gave rise to 2.095 g (54.4%) of benzo[b]thiophene 27a. mp 113115'. Recrystallization of fractions 19-25 (total 0.28 g) afforded 0.26 g (6%) of 28 as light yellow needles, mp 171-172'. Formation of 3,4-Dichloro-5-methoxy-2-methoxycarbonylbenzo[ blthiophene (28) from 3-Chloro-2-chlorocarbonyl-5methoxybenzo[ blthiophene (27b). A mixture of 1.044 g (4 mmol) of 27b (mp 147.3-148.3') and 5 ml of thionyl chloride was heated at reflux (bath temperature 95') for 24 hr. Excess thionyl chloride was removed, and the product was treated with 50 ml of absolute methanol a t reflux for 10 min, concentrated, and separated on an alumina (activity grade 11, 40 g) column by eluting with benzene (seven fractions of 25 ml each). Recrystallization of fractions 1 and 2 (total 585 mg) gave rise to 345 mg (30%) of 28 as pale yellow needles, mp 170-171.5'; the infrared spectrum was identical with that of 28 previously obtained, The remaining fractions were mixtures. Reaction of Thionyl Chloride with trans-p-Nitrostilbene (31). trans-p-Nitrostilbene, mp 156-157' (lit.30mp 150-153"), was prepared by condensation of p-nitrophenylacetic acid (27.15 g) with benzaldehyde (17.50 g) in the presence of piperidine (7.5 ml) according to the method of Jambotkar and K e t ~ h a m A. ~mixture ~ of 2.14 g (9.5 mmol) of 31,O.l ml of pyridine, and 7.2 g (0.06 mol) of thionyl chloride was heated at reflux (bath temperature 100') for 48 hr. More thionyl chloride (2.4 g) was added after 24 hr. After excess thionyl chloride was removed, the residue was dissolved in 100 ml of benzene, decanted from pyridine hydrochloride, concentrated, and chromatographed on alumina (activity grade 11, 100 9). The column was successively eluted with petroleum ether-benzene (2:l) (ten fractions of 30 ml each), benzene (ten fractions of 300 ml each), and ether (four fractions of 100 ml each). Recrystallization of fractions 3-6 (total 550 mg) from 95% ethanol afforded 420 mg (15.2%) of benzo[b]thiophene 34 as yellow, fine crystals, mp 154-155'. One more recrystallization from the same solvent furnished an analytical sample: mp 155-156'; ir 6.27, 6.61, 7.48, 7.52, 11.69, 11.81, 13.05, and 13.34 pm; NMR (CDCl3) T 1.60 (d, two hydrogens ortho to nitro group, J = 9.0 Hz), 1.94 (d, two hydrogens meta to nitro group, J = 9.0 Hz), and 1.91-2.52 (complex, four aromatic hydrogens); mass spectrum mle 291, 289 (M'), 261, 259 (-NO), 245, 243 (-NO2), 233, 231 (-NO, -CO), 208 (-Cl, -NOz, base), 203, 201, 199 (-NO, -CO, -S), 164 (-NOz, -CS, -Cl), 163 (-NOz, -HCl, -CS), and 104. Anal. Calcd for C14HsClN02S: C, 58.03; H, 2.78; C1, 12.23; N, 4.83; S, 11.07. Found C, 58.07; H, 2.57; C1, 11.90; N, 4.98; S, 10.98. Recrystallization of fractions 7-9 (total 155 mg) from 95% ethanol afforded 65 mg of the starting material, mp 151-153'; mixture melting point with authentic sample showed no depression; the infrared spectrum was identical with that of stilbene 31. Fractional recrystallization of fractions 15-24 (total 1.13 g) from 95% ethanol gave rise to 530 mg of yellow crystals, mp 204-205', ir 6.64 and 7.48 pm, mass spectrum m/e 514 (M+),and 60 mg of another yellow, crystalline solid, mp 208-210°, ir 6.65 and 7.48 pm. The infrared spectra of these two products were very similar, but mixture melting point showed depression. The structures of these products have not been determined. 3-(3-Methoxyphenyl)propanoic Acid (36). m- Methoxycinnamic acid (7.13 g) in 150 ml of 95% ethanol was hydrogenated at atmospheric pressure over 10%palladium on carbon (0.4 g). The uptake ceased after 997 ml of hydrogen a t 25" (750 mm) was introduced. After the catalyst and the solvent were removed, the residue was washed with petroleum ether to yield 7.00 g (97.1%) of 36, mp 44--45O. Reaction of Thionyl Chloride with 3-(3-Methoxyphenyl)propanoic Acid. A. To a mixture of 3.60 g (0.02 mol) of 36 and 0.2 ml of pyridine was added approximately 'h of 8.0 g (0.067 mol) of thionyl chloride. The mixture was heated to 135' (bath temperature 140-145"), the rest of the thionyl chloride was added over a 1-hr period, and the mixture was stirred at this temperature for an additional 1 hr. The mixture was then treated with benzene (50 ml) and absolute methanol (25 ml) a t reflux for 30 min. After excess methanol and benzene were removed the tarry residue was separated on a column containing 150 g of neutral alumina (activity grade 111) by eluting with petroleum ether-benzene (21) (ten 50-ml fractions). Recrystallization of fractions 2-6 from 95% ethanol gave rise to 0.71 g (15.5%) of known16bbenzo[b]thiophene 37, mp 100.5-102'. One more recrystallization from the same solvent afforded white needles: mp 102.5-103.5'; ir 5.84 (C=O), 7.74 and 8.18 (C-01, and 8.66 pm; NMR (CDCl3) ca. T 2.06 (d, H3, J = 0.7 2.92 Hz), 2.31 (tripled doublet, H7, J = 8.6, 0.7 Hz), 2.75 (m, H4), (dd, H6, J = 8.6, 2.5 Hz), and 6.07 and 6.16 ( 2 s, 2 OCH3); mass
3044
J . Org. Chem., Vol. 40, No. 21,1975
Higa and Krubsack
spectrum mle 224,222 (M+, base), 207 (-CH3), 191 (-OCH3), 179 separated on an alumina (basic, activity grade I, 100 g) column by (-CH3, -CO), 163 (-OC&, -CO), and 148 (-CH3, -COzCHs). eluting with 500 ml of petroleum ether-ether (10;3) to yield 6.89 g B. A mixture of 2.70 g (0.015 mol) of acid 36,0.15 ml of pyridine, (38%) of ethyl m-diethoxymethylcinnamate: bp 126-130' (0.04 and 12.0 g (0.1 mol) of thionyl chloride was heated a t reflux (bath mm); ir (neat) 3.34 (C-H), 5.86 (C=O), 6.11 (C=C), and 7.72,7.98, temperature 100') for 46 hr. Excess thionyl chloride was destroyed and 8.55-8.70 pm ((2-0); NMR (CDC13) T 2.24 and 3.49 (2 d, two vinyl hydrogens, J = 16 Hz), 2.27-2.52 (m, four aromatic hydroby careful addition of methanol. The mixture was dissolved in 70 ml of dry benzene and 30 ml of absolute methanol, heated under gens), 4.45 (s, one methine hydrogen), 5.70 (4, CH2, J = 7.0 Hz), reflux for 30 min, filtered to remove a small amount of insoluble 6.30 (9, 2 CH2, J = 7.0 Hz), 8.66 (t, CH3, J = 7.0 Hz), and 8.74 (t, 2 CH3, J = 7.0 Hz). material (sulfur), and evaporated t o remove solvent and excess Ethyl 3-(3-Diethoxymethylphenyl)propanoate.The unsatumethanol to yield 4.48 g of a mixture of solid products. The mixture was placed on an alumina (activity grade 111, 150 g) column rated ester (4.41 g) was reduced with atmospheric hydrogen over 0.5 g of Raney nickel (W-2) in 25 ml of absolute ethanol. After the and eluted with petroleum ether-benzene (21) to afford 32 fractions (50 ml each for fractions 1-22 and 100 ml each for 23-32). catalyst was removed by filtration, the ethanolic solution was conFractions 1 and 2 gave 85 mg of sulfur. Each of the fractions 4 centrated to yield 4.37 of crude ester. The crude product was dis(105 mg) and 5 (160 mg) was recrystallized from 95% ethanol to tilled to afford 4.075 g (91%) of pure ethyl 3-(3-diethoxymethylpheny1)propanoate as a colorless oil: bp 105-108' (0.06 mm); ir yield a total of 130 mg (3%) of benzo[b]thiophene 39 as white, fine crystals: mp 138-138.5'; ir 5.83 (C=O), 6.68, 7.71 (C-0), and 9.32 (neat) 3.32 (C-H), 5.75 (C=Q), 8.65 (C-0), and 9.52 pm; NMR T 2.71-2.92 (m, four aromatic), 4.54 (s, one methine), 5.91 and 6.48 (2 pm; NMR (CDCl3) T 1.88 (s, H3), 2.56 (s, H5), and 5.93 and 6.01 (2 s, 2 OCH3); mass spectrum mle 292, 290 (M+, base), 277, 275 q, 3 OCH2, J = 7.0 Hz), 6.90-7.52 (m, 2 CH2), and 8.77 (t, 3 CH3, J = 7.0 Hz). (-CH3), 261, 259 (-OCH3), 249, 247 (-CH3, - e o ) , 218, and 216 (-CH3, -C02CHs). 3-(3-Formylphenyl)propanoicAcid (45). Ethyl 3-(3-diethoxyAnal. Calcd for CllHsC1203S: C, 45.38; H, 2.77; C1, 24.35; S, methylpheny1)propanoate (4.00 g) was heated with 20 ml of 1 N 11.01. Found: C, 45.30; H, 2.60; C1, 24.62; S, 10.73. sodium hydroxide solution and 25 ml of methanol on a steam bath. Recrystallization of fraction 6 (275 mg) from 95% ethanol affordAfter most of the methanol was evaporated, the aqueous solution ed 55 mg (1.3%) of compound 38 as pale yellow needles: mp 174was cooled, extracted with ether, and acidified with 1 N hydrochloric acid (25 ml). The resulting emulsion was heated to form a 174.5'; ir 5.80 (C=O), 6.56, 7.94, and 8.15 pm (C-0); NMR (CDC13) T 1.85 (s, H3), 2.80 (s, H6), and 6.01 (s, 2 OCH3); mass clear solution, cooled, and extracted with ethyl acetate, dried (MgS04), and concentrated to yield 2.79 g of the crude acid. The spectrum mle 292, 290 (M+, base), 277, 275 (-CH3), 261, 259 (-OCH3), 249, 247 (-CH3, -CO), 233, 231 (-CO&H3), 218, and crude product was distilled to afford 1.93 g (76%) of the acid 45: bp 147-148' (0.06 mm); NMR (CDC13) T -1.63 (s, COOH), -0.03 (s, 216 (-CH3, -C02CH3). CHO), 2.20-2.53 (m, aromatic), and 6.73-7.40 (m, 2 CH2). Anal. Calcd for CllHgC1203S: C, 45.38; H, 2.77; C1, 24.35; S, Reaction of Thionyl Chloride with (3-(3-Formylphenyl)11.01. Found: C, 45.51; H, 2.55; C1, 24.34; S, 10.78. propanoic Acid (45). To a mixture of 1.82 g (0.0102 mol) of 45 Recrystallization of fractions 8-29 (total 2.61 g) from 95% ethaand 0.1 ml of pyridine was added approximately half of 5.0 g (0.041 nol yielded 2.16 g (56%) of benzo[b]thiophene 29 as white needles, mol) of thionyl chloride. The mixture was heated to 140' (bath mp 160-162'; both infrared and NMR spectra were identical with temperature), and the rest of the thionyl chloride was added at those of 29 obtained by the reaction of the acid 26. 140-145' over a period of 45 min. The mixture was heated at this Anal. Calcd for CllH9C103S: C, 51.45; H, 3.53; C1, 13.81; S, 12.49. temperature for an additional 1 hr. After cooling 5 ml of absolute Found: C, 51.51; H, 3.32; C1, 13.67; S, 12.64. methanol was added, and the mixture was heated at reflux for 15 Isophthaloyl Dichloride. A mixture of 50 g (0.3 mol) of isomin. The precipitate (60 mg of sulfur, mp 117-118') was removed phthalic acid and 120 g (1 mol) of thionyl chloride was stirred a t by filtration, and excess methanol was evaporated. The residue reflux. The evolution of hydrogen chloride was very slow until 2 ml was chromatographed on an alumina (activity grade 111,100 g) colof pyridine was added. The mixture was heated under reflux for 5 umn by eluting with petroleum ether-benzene (5:l) (ten 50-ml hr. After excess thionyl chloride was removed the product was disfractions) and with a 1:l mixture (five 250-ml fractions). solved in 300 ml of hot hexanes, filtered to remove pyridine hydroFraction 1 was 40 mg of sulfur. Each of the fractions 2-6 (total chloride, and concentrated to 150 ml. Crystallization afforded 60.0 2.32 g) was shown to be a mixture of the benzo[b]thiophenes 50a g (98.5%) of isophthaloyl dichloride, mp 44'. and 50b and the methyl ester of 46 by NMR spectroscopy. FracIsophthalaldehyde was prepared by Rosenmund reduction of isophthaloyl dichloride by the method of Hershberg and C a ~ o n . ~ ~tions 7 and 8 (total 105 mg) consisted mainly of the ester of 46. The rest of the fractions gave only small amounts of tarry material. Thus 40.6 g (0.2 mol) of isophthaloyl dichloride was allowed to Fractional crystallization of fractions 2-6 from ligroin afforded react with atmospheric hydrogen over 5.5 g of 5% palladium on 460 mg (15%) of 50b, mp 135-138', and 250 mg (8%)of 50a, mp barium sulfate and 0.5 ml of catalyst poison solution31 in 150 ml of 100-105°, Recrystallization of 50b from carbon tetrachloride afdry xylene a t reflux over a period of 4 hr. After the catalyst and xyforded colorless prisms: mp 138.5-139'; ir 5.90 (C=O), 7.64 and lene were removed the crude product was steam distilled, yielding 7.76 (C-0), and 13.64 pm; NMR (CDClS) ca. T 1.94 (dd, H4, J = 17.43 g (65%) isophthalaldehyde, mp 87-89' (lit.32mp 89'). 7.7, 1.7 Hz), 2.20 (dd, H6, J = 7.3, 1.7 Hz), 2.47 (t, H5, J = 7.7 Hz), m-Formylcinnamic Acid. A mixture of 17.43 g (0.13 mol) of 2.96 (s, CHC12), and 5.97 (s, OCH,); mass spectrum rnle 312, 310, isophthalaldehyde, 14.79 g (0.14 mol) of malonic acid, 35 ml of pyr308 (M+), 277, 275, 273 (-Cl, base), 242 (-Cl, -OCH3), 216, 214 idine, and 35 ml of 95% ethanol was heated under reflux over a pe(-Cl, -C02CH3), 181, 179 (-2 C1, -C02CH3), 144 (-3 C1, riod of 9 hr. The mixture was cooled and 90 ml of 6 N hydrochloric -C02CH3), 122, and 121. acid was added. The precipitate was filtered, washed with 500 ml Anal. Calcd for CllH7C1302S: C, 42.68; H, 2.28; C1, 34.35; S, of water, and dried under vacuum at 80' overnight to yield 18.50 g 10.36. Found: C, 42.61; H, 2.34; C1,34.11; S, 10.19. of a mixture. The mixture was separated by extraction with chloroCompound 50a was recrystallized from ligroin, affording colorform in a Soxhlet extractor t o yield 12.66 g (55.3%) of m-formylcinless plates: mp 104.5-105.5'; ir 5.80 (C=O), 6.62, 8.02, and 8.11 namicacid (monoacid),mp 189-191°,and3.62g (12.8%)of 1,3-bis(2(C-0), 9.48, and 13.54 pm; NMR (CDC13) T 1.88 (finely divided carboxyethenyl)benzene, mp 285-288' (lit.33 mp 277') which resinglet, H4), 2.12 (finely divided singlet, H6 and H7), 3.08 (s, mained in the thimble. An analytical sample of the monoacid, mp CHClz), 5.98 (s, OCH3); mass spectrum mle 312, 310, 308 (M+), 190-192', was obtained by recrystallization from chloroform. 277, 275, 273 (-Cl, base), 242 (-Cl, -OCH3), 216, 214 (-Cl, Anal. Calcd for C1&@3: C, 68.18; H, 4.58. Found: C, 67.89; H, -C02CH3), 181, 179 (-2 C1, -C02CH3), 144 (-3 C1, -COzCH3), 4.73. 122, and 121. Ethyl m-Diethoxymethylcinnamate. In a 500-ml round-botAnal. Calcd for CllH7C1302S: C, 42. 68; H, 2.28; C1, 34.35; S, tomed flask equipped with a condenser, Dean-Stark trap, and a 10.36. Found: C, 42.80; H, 2.06; C1,34.17; S, 10.10. drying tube was placed 11.40 g (0.064 mol) of n-formylcinnamic Reaction of Thionyl Chloride with rn-Formylcinnamic acid, 130 ml of absolute ethanol, and 0.5 ml of concentrated sulfuAcid. A mixture of 3.52 g (0.02 mol) of m-formylcinnamic acid, 0.2 ric acid. The mixture was heated a t reflux for 10 hr, 100 ml of dry ml of pyridine, and 19.2 g (0.16 mol) of thionyl chloride was heated benzene was added, the azeotropic mixture was distilled, and more a t reflux (bath temperature 98-100') for 48 hr. After excess thionethanol (100 ml) was added. The process of reflux, addition of benyl chloride was removed the residue was stirred with 15 ml of absozene, and azeotropic distillation was repeated. To the final reaclute methanol a t room temperature for 30 min. The methanolic sotion mixture in 100 ml of dry benzene was added 30 ml of 2 N sodilution was poured into a flask containing 100 ml of dry carbon tetum hydroxide solution with stirring at the freezing point of benrachloride, filtered to remove pyridine hydrochloride, and concenzene. The layers were separated, and the benzene layer was washed trated to furnish a mixture of products. The mixture was fractionwith saturated sodium bicarbonate solution, concentrated, and
J. Org. Chem., Vol. 40, No. 21,1975 3045
Reaction of Thionyl Chloride with Cinnamic Acids ally crystallized f r o m ligroin t o afford 2.00 g (32.3%) o f 50b, mp 130-135’; recrystallization f r o m chloroform gave prisms, mp 137.5-138.5’. T h e infrared spectrum was identical w i t h t h a t of 50b obtained f r o m the reaction o f 45. Crystallization f r o m t h e mother liquor after separation of 50b furnished 0.84 g (13.5%) o f 50a, mp 104-106’; m i x t u r e melting p o i n t w i t h 50a previously obtained showed n o depression.
Acknowledgment. This work was supported in part by a grant (GP 31761 X) from the National Science Foundation.
Chem., 21 1853 (1968); (b) N. B. Chapman, D. F. Ewing, R. M. Scrowston, and R. Westwood, J. Chem. Soc. C, 764 (1968). (17) As described in most textbooks of infrared spectroscopy, substituted benzenoid components show definite absorption patterns in the 5-6-km region depending on the number and relative positions of substituents. Since 22a and 3-chloro-6-nitrobenzo[ b] thiophene can be regarded as 1,2,4-trisubstituted benzenes and 22b and 3-chloro-7-nitrobenzo[ blthiophene as 1,2,3-trisubstituted benzenes, their spectra were compared and showed good correlation. (18) (a) D. Seyferth, W. Tronich, R. S. Marmor, and W. E. Smith, J. Org. Chem., 37, 1537 (1972); (b) H. Staudinger and J. Slegwart, Helv. Chim. Acta, 3, 840 (1920); (c) A. Schonberg and L. v. Vargha, Justus Liebigs Ann. Chem., 483, 176 (1930); Ber., 64, 1390 (1931). For related reactions, see also (d) T. J. Barton and R. G. Zika, J. Org. Chem., 35, 1729 (1970); (e) J. R. Collier and J. Hill, Chem. Commun., 640 (1969). (19) The orientation of the addition of thionyl chloride across the double bond of 31 would be exclusively to form i which then would undergo Pummer-
R e g i s t r y Na.-3, 39252-24-9; 4, 21815-91-8;5, 56030-35-4;9, 140-10-3;11, 107-93-7;12,51656-69-0; 13,56030-36-5; 20,1772-765; 21a, 34674-00-5;21b, 41280-78-8;22a, 41280-79-9;22b, 41280C1 CI 80-2;26, 17570.26-2;27a, 41280-81-3; 27b, 56030-16-1; 28, 4128082-4;29,41280-83-5; 30,41280-84-6; 31, 1694-20-8;34,41280-85-7; 36, 10516-71-9;37, 19492-99-0; 38, 56030-17-2;39, 56030-18-3;45, I s=o 56030-19-4;50u, 56030-20-7;50b, 56030-21-8;t h i o n y l chloride, I I 7719-09-7;cinnamoyl chloride, 17082-09-6;trans-crotonyl chloC1 ride, 625-35-4;trans-2-chloro-2-butenoylamide, 56030-37-6;3i chloro-7-nitro~enzo[b]thiophene, 56030-22-9;trans-rn-methoxyer rearrangement to form sulfenyl chloride 32. For examples of Pumcinnamoyl chloride, 56030-38-7;trans-rn-methoxycinnamic acid, merer reaction of sulfoxides without @-ketogroups, see (a) L. Horner 17570-26-2; isophthaloyl chloride, 99-63-8; isophthalic acid, 121and P. Kaiser, Justus Liebigs Ann. Chem., 626, 19 (1959); (b) W. E. Pa91-5;isophthalaldehyde, 626-19-7; rn-formylcinnamic acid, 56030rham and L. D. Edwards, J. Org. Chem., 33, 4150 (1968); (c) G. A. Rus23-0;malonic acid, 141-82-2;e t h y l rn-diethoxymethylcinnamate, sell and G. J. Mikol, Mech. Mol. Migr., 1, 157 (1968). 56030-24-1;e t h y l 3-(3-diethoxymethylphenyl)propanoate,56030(20) F. Loth and A. Michaelis, Chem. Ber., 27, 2540 (1894). The reaction of benzaldehyde with thionyl chloride was repeated and found to be slow 19-4.
References and Notes Taken in part from the Ph.D. Dissertation of T.H., The Ohio State University, Columbus, Ohio, 197 1. Preliminary communication: A. J. Krubsack and T. Higa. Tetrahedron Lett., 125 (1973). A. J. Krubsack and T. Higa, Tetrahedron Lett.. 5149 (1968). A. J. Krubsack, T. Higa, and W. E. Slack, J. Am. Chem. Soc.. 92, 5258 (1970). G. A. Russell, 0.Rep. Sulfur Chem., 3, 163 (1968). A. J. Krubsack and T. Higa, Tetrahedron Lett., 4515 (1973). M. S. Simon, J. B. Rogers, W. Saenger, and J. Z. Gougoutas, J. Am. Chem. Soc., 89, 5838 (1967). F. Effenberger and J. Daub, Angew. Chem.. 76, 435 (1964); Chem. Ber., 102, 104 (1969). S. Patai and A. Patchornik, J. Am. Chem. Soc., 74, 4494 (1952); S. Patal and F. Hergmann, J. Am. Chem. Soc., 72, 1034 (1950). R. N. McDonald and R. A. Krueger. J. Org. Chem., 28,2542 (1963). The role of pyridine, which immediately forms pyridine hydrochloride by combining with liberated hydrogen chloride, is believed to be promoting the polarization of thionyl chloride. A participating role of pyridine, such as described for the thionyl chloride-pyridine conversion of maleimide to dichloromaleimide.i2 may also be operative. H. M. Relles. J. Org. Chem., 37, 3630 (1972). J. R. A. Pollock and R. Stevens, Ed., “Dictionary of Organic Compounds,” 4th ed, Oxford Universi Press, London, 1965, p 612. Our initially proposed mechanism for the formation of 4 from 1involved an electrophilic substitution reaction of 2 to form benzo[b]thiophene-2carbonyl chloride, which was then chlorinated at the C-3 position to yield 4. Treatment of benzo[b]thiophene-2-carboxylic acid, prepared by an unambiguous rnethod.l5 with thionyl chloride in the presence of pyridine for 6 hr at 135-140’ and for an additional 10 hr at reflux furnished 4 in 21 % yield. The rest was unchanged starting material. On the other hand, treatment of 1 with thionyl chloride and pyridine at 130-140’ for 4.5 hr afforded 4 in 56.2% yield. The slow reaction rate and the diminished yield of 4 in the former experlment revealed that our initial mechanism was incorrect. T. Higa and A. J. Krubsack, in preparation. For NMR spectra of substituted benzo[b]thiophenes, see (a) B. Caddy, M. Martin-Smith, R. K. Norris, S. T. Reid, and S. Sternhell, Aust. J.
2
without catalyst at reflux. However, the reaction could be made faster by introducing a small amount of pyridine. (21) Acid 45 was prepared as follows. Rosenmund reduction of isophthaloyl dichloride gave isophthaldehyde, which was treated with 1 equiv of malonic acid in pyridine to yield m-formylcinnamic acid. The latter was converted to ethyl m-diethoxymethylcinnamate upon treatment with absolute ethanol in the presence of concentrated sulfuric acid. Reduction of the acetal ester with Raney nickel followed by saponification and then acid hydrolysls gave acid 45. (22) The distance between chlorine and the perihedral hydrogen atom in 51 is measured as 2.53 A b drawing the structure in which bond angles of 120’ and bond lengthsA as indicated are assumed. This distance is 0.47 A shorter than the sum of the Van der Waals radii of chlorine (1.80 A) and hydrogen (1.20 A). Bond lengths, 1083
A
1.4%
1.337
C1
172
2.53 51
(23) Taken from “Interatomic Distances Supplement”, Chem. Soc., Spec. Pub/.. No. 18 11965). (24) Both sulfenyl chlorides 12 and 18b were approximately 1:l mixtures of diastereomers, as indicated by the NMR spectra. (25) J. Hine, “Physical Organic Chemistry”, 2nd ed, McGraw-Hill, New York. N.Y.. 1962, p 211; S. J. Cristol, Acc. Chem. Res., 4, 393 (1971). (26) The reaction of thionyl chloride with esters will be reported elsewhere. (27) L. Friedman and W. P. Wetter, J. Chem. SOC.A, 36 (1967). (28) We thank Mr. Weissenberger for the mass spectra measurements, ana the National Science Foundation for a grant (GP 5202) to the Chemistry Department of The Ohio State University for the mass spectrometer. (29) L. F. Fieser, “Organic Experiments”, 2nd ed, Raytheon Education Co., Lexington, Mass., 1968, p 231. (30) D. Jambotkar and R. Ketcham, J. Org. Chem., 26,2182 (1963). (31) E. B. Hershberg and J. Cason, “Organic Syntheses”, Collect. Vol. 111, Wiley, New York, N.Y., 1955, p 627. (32) P. Couturier and S. Fraldenrajch, Bull. SOC.Chim. Fr., 318 (1958). (33) W. Ried and F. J. Konigstein, Chem. Ber., 92, 2532 (1959).
