J. Org. Chem. 1984,49,3891-3898 10 Hz), 4.15 and 4.03 (1H, each, AB,, J = 10 Hz, C&OTS), 3.93 (4H, m), 3.72 (3H, s), 2.40 (3H, s), 2.0-1.4 (4H, m); MS, m l e (%) 258 (40, M - TsOH), 2.45 (60,M - CHZOTs), 107 (100). 8-(Cyanomethyl)-8-(4-methoxyphenyl)-l,4-dioxaspiro[4.5]dec-6-ene (110). The tosylate lld (50 mg) and sodium cyanide (250mg) were dissolved in HMPA (5mL) in a tightly stoppered flask,purged with nitrogen, and heated a t 155 "C for 17 h (oil bath). The cooled mixture was diluted with ether, washed thoroughly with water, dried (Na2C03),and evaporated. The crude product was subjected to preparative TLC (10% ethyl acetate in benzene) to give pure nitrile lle (19 mg, 60%): Y(CHC13) 2260,1650,1605,1585 cm-l; b (CDC13, 400 MHz) 7.25 (2H, d, J = 9 Hz), 6.87 (2H, d, J = 9 Hz), 6.09 (1H, d, J = 10 Hz),5.89 (1 H, d, J = 10 Hz),4.05-3.9 (4H, m), 3.79 (3H, 8, OMe), 2.78 and 2.67 (1 H each AB,, J = 16.6 Hz, CH2CN), 2.08 (2 H, m), 1.75 (1H, m), 1.67 (1H, m); MS, m l e (%) 285 (l),284 (ll), 245 (85),173 (100);found M+ 285.2651,calcd for Cl7HlsNO3M+ 285.2667. 4-(Cyanomethyl)-4-(4-methoxyphenyl)-2-cylohexenone (6). A stock solution of dioxane (5mL), methanol (3mL), water (1 mL), and concentrated hydrochloric acid (2drops) was prepared. The nitrile lle (10mg) was dissolved in this solution (2mL) and stirred at room temperature for 6 h. The mixture was diluted with ether (20 mL), washed with water (3 X 10 mL), dried
3891
(MgSO,), evaporated, and purified by preparative TLC to afford 6 (6mg, 72%): ,Y (CHCld 2250,1685,1625cm-'; 6 (CDCl, 200
MHz),7.26(lH,d,J=lOHz),7.14(2H,d,J=9Hz),6.90(2 H, d, J =9 Hz), 6.25 (1 H, d, J = 10 Hz), 3.79 (3 H, s), 2.80 (2 H,close AB,, CHZCN), 2.e1.6 (4H, m); MS, m l e (%) 241 (17), 201 (loo),173 (50),149 (30);found M+ 241.1120,calcd for C15H15NO2 M+ 241.1103. Acknowledgment. Financial support of this research b y SERC a n d Beecham PharmaceutiGals (CASE studentship t o I.C.R.) (U.K.) is gratefully acknowledged. Essential equipment was purchased with grants from t h e National Institutes of Health (GM30373), and the National Science Foundation (CHE80-24633, toward purchase of Varian XL-200 N M R spectrometer). Registry No. lb, 51508-59-9;(*)-6, 79214-94-1;(&)-7, 91817-43-5;(*)-8 (isomer l), 83917-60-6;(*)-e (isomer 2), 83875-21-2;(&)-lo,91817-44-6;(&)-lla,83925-42-2;(&)-llb, 83925-44-4; (&)-llc,83925-45-5;(*)-lld,83925-46-6; (i)-lle, 83925-47-7;(i)-12(isomer l), 83917-59-3;(&)-12 (isomer 2), 83875-22-3; 14,67019-46-9;methyl (*)-1-(4-methoxyphenyl)-2oxo-3-cyclohexenecarboxylate, 91817-45-7;3-methoxy-2-cyclohexenone, 16807-60-6.
Selective Reductions. 35. Reaction of Representative Organic Functional Groups with Lithium Borohydride in the Presence of B-Methoxy-9-borabicyclo[3.3.l]nonane. A Simple, Convenient Procedure for the Catalyzed Selective Reduction of Esters Herbert C. Brown* a n d S. Narasimhan Richard B. Wetherill Laboratory, Purdue University, West Lafayette, Indiana 47907 Received February 1, 1984
The rate of reduction of esters by lithium borohydride is considerably enhanced by a number of Lewis acids of boron. The remarkable catalytic effect of B-MeO-9-BBN and (Me0)3B in enhancing the reactivity of lithium borohydride toward the reduction of other representative functional groups has been explored. Alkyl halides are not reduced. Epoxides are readily reduced in 0.25 h. Carboxylic acids are reduced rapidly up to 50%,with further reaction being very slow. Acid salts are not reduced. Tertiary amides are slowly reduced in the presence of 100 mol % of B-MeO-9-BBN, 40% in 24 h. Nitriles, under the same conditions, are reduced completely in 5 h. Pyridine and nitrobenzene are not significantly affected by this system. Sulfides, sulfoxides, and sulfones are also inert. However, tosylates are reduced rapidly. These results indicate the utility of this catalytic effect for the ready reduction of esters by lithium borohydride, as well as the ability of this reducing system to tolerate many Substituents in such reductions. Sodium borohydride is a mild reducing agent.' However, the reducing potential of borohydride can be modified b y proper choice of reaction conditions.' The important factors which affect the reactivity of borohydride a r e (1) solvent, (2) cation, (3) use of catalysts,and (4) the presence of activating substituents. W e have studied the effect of solvent and cation on the rate of reduction of esters by borohydridea2 The results indicated that lithium borohydride in ethyl ether is a powerful reducing system for esters. We y m e s s f u l l y employed this system for the synthesis of alcohols from esters.2 However, a t t e m p t s to reduce unsaturated esters t o t h e corresponding alcohols were not successful. A more systematic s t u d y of t h e reduction of an unsaturated ester, ethyl 10-undecenoate, revealed t h a t the uptake of hydride b y this ester was far (1) Schlesinger, H.I.; Brown, H. C.; Hoekstra, H. R.; Rapp, L. R.J . Am. Chem. SOC.1953, 75, 199. ( 2 ) Brown, H . C.; Naraeimhan, S.;Choi, Y. M. J.Org. Chem. 1982,47, 4702.
faster than t h e uptake by t h e saturated ester, ethyl cap3 mmol of hydride are utilized per mmol of r ~ a t e . Also, ~ ester, compared to 2 mmol of hydride utilized by ethyl caproate a n d similar saturated carboxylic esters. T h e reduction product, following oxidation, was a mixture of 1,ll-undecandiol (85%)and 1,lO-undecandiol (15%) (eq 1).
+
HOCH2(CH2)&H20H "' 85% CH3CHOH(CH2)&H20H (90% overall yield) (1) 15% This unexpected greater reactivity of t h e unsaturated ester prompted u9 to investigate this phenomenon in detail, resulting i n t h e discovery of new powerful catalysts for enhancing t h e reactivity of lithium b ~ r o h y d r i d e . ~W e ( 3 ) Brown, H . C.; Narasimhan, S . Organometallics 1982, I , 762.
0022-326318411949-3891$01.50/0 0 1984 American Chemical Society
3892 J. Org. Chem., Vol. 49, No. 21, 1984
Brown and Narasimhan
present here in detail our studies on the explorationof such catalysts and their utility for the selective reduction of esters and other derivatives.
Results and Discussion Procedure for Rate and Stoichiometric Studies. In a typical reaction, 5 mmol of borohydride in the appropriate solvent was treated with 5 mmol of the ester at 25 "C. The total volume of the solution was adjusted to 5 mL. The resulting solution becomes 1 M in borohydride and 1M in ester. In cases where clear solutions were realized, the course of the reaction was followed by determining at various time intervals the concentration of residual borohydride in aliquots of the reaction mixture. A blank reaction was performed under identical conditions, but without addition of compound. From the differences in the amounts of hydrogen evolved in these two experiments, the mmol of hydride used for reduction per mmol of compound were calculated. In cases where the reaction mixture was a slurry, the rate was followed by conducting the experiment under identical conditions in individual flasks, hydrolyzing the entire reaction mixture to obtain the residual hydride concentration. Effect of Alkene on the Rate of Reduction of Esters by Lithium Borohydride in Ether. Our studies on the reduction of the unsaturated ester, ethyl 10-undecenoate, indicated concurrent hydroboration of the double bond. Alkenes are normally inert to the action of lithium borohydride. consequently, the reduction of the ester grouping must in some way activate the lithium borohydride reagent so that it can hydroborate the carbon-carbon double bond. It was of interest to examine whether the same phenomenon would be observed if the carbon-carbon double bond were contained in a separate molecule. Accordingly, the rate of reduction of ethyl caproate by lithium borohydride in ethyl ether in the presence of an equimolar concentration of 1-decene was examined. Indeed, we observed a very fast uptake of 3 equiv of hydride (30 min) with complete reduction of the ester and complete hydroboration of the alkene (Figure 1) (eq 2). CH3(CH2)4COOEt + CH3(CH2),CH=CH2+
b-1 b
r 5
2
U
1 ,
2
I
Time (h)
-
3
4
Figure 1. Reduction of ethyl caproate by LiBH, in ether at 25 O C in the presence of 1-decene: [ester] = 1 M; [LiBHJ = 1 M; [I-decene] = 1 M.
t
3l
I
/-'IoM'
I
2
Time (h)
-
3
4
Figure 2. Reduction of ethyl caproate by LiBHl in ether at 25 " C in the presence of various concentrations of 1-decene: [ester] = 1 M; [LiBH4] = 1 M; [I-decene] = 1, 0.2, 0.1, and 0.05 M.
The rate enhancement in the presence of alkene could be accounted for in terms of the following mechanism. The usual reaction in the absence of alkene would involve a hydride transfer from the borohydride anion to the carbonyl group (eq 3). In the presence of alkene, the transfer 0
I1 + R-C I Et0
08HBH3-
I! I Et0
8-
R-C---H---BH,
SlOr
products
(3)
1
of hydride could be facilitated by a concurrent reaction of the leaving group, borane, with the alkene (eq 4). 0
H---CHR'
Et0
This scheme would predict a rate enhancement by amines capable of taking up b ~ r a n e . Accordingly, ~ the (4) Brown, H. C.;
Narasimhan, S. J. Org. Chem. 1982, 47, 1604.
rate of reduction of ethyl caproate (1M) by LiBH4 (1M) in ether was studied in the presence of 20 mol % of pyridine (0.2 M). The initial rate up to 20% was quite rapid. Thereafter, it followed the normal rate. I1B NMFt analysis of the reaction mixture confirmed the presence of pyridine-borane, 6 -11 (9). Surprisingly, use of even catalytic amounts of 1-decene accelerated the rate up to the completion of reaction (Figure 2). Since olefin would have reacted in the beginniig of the reaction, the hydroborated species produced must also exert a catalytic effect. Consequently, we studied the stoichiometry and product of the reaction between an alkene, ester, and LBHI. The mechanism will be discussed in more detail later in this publication. Stoichiometry and Product of Reaction of 1-Decene with LiBH4in the Presence of Ethyl Caproate. It is evident from Table I that a maximum of 3 mol of 1-decene are hydroborated by LiBH4for each mole of ester reduced. Similar results were obtained with ethyl acetate. On this ( 5 ) Brown, H. C.; 1966, 77,6209.
Mead, E. J.; Subba Rao, B. C. J.Am. Chem. SOC.
J. Org. Chem., Vol. 49, No. 21, 1984 3893
Selective Reductions Table I. Stoichiometry of the 1-Decene-Catalyzed Reduction of Ethyl Caproate by Lithium Borohydride in Ether at 25 O c a residual reactants LiBH4; olefin: ester, LiBH4, olefin, ester: mmol mmol mmol mmol mmol mmol 3.63 6 0.18 0 1 1 3.04 6 0 0 1 1.25 6 0 0.75 3.02 1 2 3.05 6 0 4.76 1 6 0.06e 3 0 0 1 1.25
100.
80
t
.-5
ti
a
8
‘Reaction time, 8 h. bAnalyzed by GLC after oxidation using Carbowax 10% 20M on Chromosorb W,6 ft X in. ‘Estimated by hydrolysis method. dDetermined by ‘HNMR using benzene aa internal standard. ellB NMR showed two peaks: 6 8 and 2.6. Table 11. Rate of Reduction of Ethyl Caproate by LiBH, in the Presence of Various Catalysts in Ether at 25 % reaction catalyst 0.5h I h 2 h 4 h 8 h 24h no catalyst 17 28 41 65 100 100 LiEbBH 80 100 100 Li-9-BBNH 100 100 LiEhBOMe 83 98 100 LiB(OMe)*-g-BBN 100 100 BF3*OEt, 21 35 50 73 100 100 BH,*THF 10 14 18 26 53 62 n-Bu3B 22 98 100 B-OMe-9-BBN 100 103 n-octB(OMe)2 92 100 (MeOhB 52 100 (PhOhB 14 30 45 68 98 (n-DodO),B* 26 46 100 a [Ester] = 1.0 M; [LiBH4] = 1.0 M; [catalyst] = 0.1 M. bn-Dod = n-dodecyl.
basis, the stoichiometric equation could then be that shown in eq 5. However, llB NMR analysis of the reaction CH,COOEt + 3R’CH=CH2 5/4LiBH4 LiBR30Et + 1/4LiB(OEt)4( 5 )
-
+
mixture showed two peaks around 6 8 and 3. Hydrolysis of this mixture and analysis of the ether layer indicated two peaks corresponding to the presence of both trialkylborane and borinic ester: 6 87 (R3B, 40%) and 54 (R2BOR’,60%). Hence the reaction would be better expressed by the following equation (eq 6). CH3COOEt 3R’CH=CH2 + 6/4LiBH4 3/4LiBRz(OEt), l / 2LiBR30Et (6)
+
+
-
New Powerful Catalysts for the Reduction of Esters by LiBHa in Ether. Since the products of hydroboration of olefin are LiBR2(0R)2and LiBR3(OR’), the catalytic effect could be due to either or both of these species. This indicates that addition of LiEt3BOR’ or LiB(OR’I2-9-BBNwould catalyze the reaction. Also, since these species are produced in the reduction of esters by LiEt3BH or Li-9-BBNH, catalytic amounts of these hydride reagents should also enhance the rate of reduction of esters by LiBH4. Indeed, the presence of 10 mol % of these species remarkably catalyzes the reduction of ethyl caproate by LiBH4 (Table 11). It appears that these catalysts must produce species capable of enhancing the reaction, being regenerated under the reaction conditions. We deduced that the recycling intermediates must be Et3BB“and B-OR’-g-BBN, based on the following equilibrium in ether (eq 7). LiBR30R’ + LiOR’ + BR3 (7) We used both tri-n-butylborane and B-OMe-9-BBN and confirmed this prediction (Table 11). Indeed, we discovered
~
60-
40-
20
-
olko CH3COONo CBOMc
0
10
Time (h)-
Figure 3. Reduction of epoxide, carboxylic acid, and salt by LiBH4 in ether at 2k “Cin the presence of catalyst: [substrate] = 1 M, [LiBH4] = 1 M.
that B-OMe-9-BBN is a far more powerful catalyst than n-Bu3B or any of the other species examined (Table 11). Since B-OMe-9-BBN exhibits an exceptionally powerful catalytic effect and (MeO),B possesses a major advantage, ready removal from the reaction mixture by simple washing with water, we emphasized these reagents for synthetic applications. Accordingly, preliminary rate studies were made for representative esters in ether and THF. The results are presented in Table 111. Evidently, ether is advantageous as the solvent medium. Hence, we studied the reduction of various organic functional groups in the presence of the catalysts, B-OMe-9-BBN or (MeO),B, in ether. Reduction of Representative Organic Functional Groups by LiBH4in Ether. Since aldehydes and ketones are readily reduced by lithium borohydride, we did not attempt to study the effect of catalysts on the reduction of these functional groups. However, we examined the reduction of other less reactive substrates, both in the presence and absence of the catalyst. The general procedure for rate measurements was followed by using solutions of l M in compound and l M in borohydride. The amount of catalyst used was 10 mol 9%, unless otherwise indicated. Reduction of Alkyl Halides. The reduction of alkyl halides, such as n-octyl bromide, was not significantly enhanced by the presence of the boron catalysts. Reduction of Epoxides. Cyclohexene oxide was reduced quite rapidly (1 h) by LiBH.,, In the presence of 10 mol % B-OMe-9-BBN, the reduction was complete in 15 min (eq 8) (Figure 3). It has also been shown that the
1W
1W
0.1 AI
reduction of epoxides by LiBH4 is catalyzed by Et3B.6b Similar results have also been reported for the reaction of (6) Professor N. M. Yoon of Sogang University, Seoul, Korea, has informed us that he and his students have observed a catalytic effect of triethylboraneon the reduction of eaters and epoxides by lithium borohydride in THF. (a) Yoon, N. M.; Park, H. M.; Cho, B. T.; Oh, I. H. Bull. Korean Chem. SOC., submitted for publication. (b) Yoon, N. M.; Oh, I. H.; Choi, K. I.; Lee, H. J. Heterocycles, submitted for publication.
3894 J. Org. Chem., Vol. 49, No. 21, 1984
Brown and Narasimhan
Table 111. Reduction of Selected Esters by LiBH," Catalyzed by B-Methoxy-9-BBN or Methyl Borate % reaction ester catalyst solvent temp, "C 0.5 h 1h 2h 4h 8h ethyl caproate none ether 25 17 41 28 65 100 103 ether 25 B-OMe-9-BBN 100 ether 25 52 100 100 B(OMe), 41 none 61 26 ether 35 90 99b 101 ether 35 B-OMe-9-BBN l00C 100 ether 35 l00d B(OMeh 10 THF 25 none 5 21 29 48 B-OMe-9-BBN 25 35 THF 25 48 65 97 THF 25 33 60 86 B(OMe), 53 THF 65 none 100 101 37 76 B-OMe-9-BBN THF 65 101 80 104 67 THF 65 100 100 93 B(OMeh 9 14 ether 25 ethyl benzoate none 19 49 31 52 a2e ether 25 100 B-OMe-9-BBN 15 ether 25 70' 45 96 30 B(OMeh ether 35 44 20 12 30 67' none ether 35 102 B-OMe-9-BBN 100' 60 ether 35 29 65 100 46 86' B(OMeh THF 25 20 none 12 32 THF 25 56 B-OMe-9-BBN 68 27 45 THF 25 36 45 27 8 B(OMe13 THF 65 67 45 100 33 none 88 104 100 54 B-OMe-9-BBN THF 65 100 80 THF 65 50 B(OMeh ether 25 ethyl pivalate none lsl 21 35 10 7 24 ether 25 76 B-OMe-9-BBN 43 59 5 ether 25 101 68 98 36 B(OMeh ether 35 45 15 none 29 9 20 74 104 ether 35 B-OMe-9-BBN 93 39 102 104 ether 35 68 B(OMe13 THF 25 4 11 l5f 2 18 none THF 25 B-OMe-9-BBN 15 25 28 34b 508 518 24 THF 25 6 13 356 B(OMe13 41b THF 65 none 10 29 488 18 54 THF 65 E-OMe-9-BBN 86 75 9sl THF 65 40 80 66 iod B(0Meh
24 h
62
e
43
[Ester] = 1 M; [LiBH4] = 1 M; [catalyst] = 0.1 M. b 5h. c0.25 h. d0.75 h. 'Solution turns cloudy. f 3 h. 812 h.
carboxylic acids with sodium borohydride in the presence of dimethyl sulfate or boron acid^.'^,^ Reduction of Carboxylic Acids. Acids liberated 1 equiv of hydrogen instantly with LiBH4. The reduction of acids was quite fast initially (50% in 30 min), but did not go to completion, even after 24 h (Figure 3). Thus, from caproic acid, only 60% of n-hexanol was isolated after 24 h. Similar results have been described for the reduction of carboxylic acids with sodium borohydride in the presence of dimethyl sulfate or boron acids (boron trifluoride etherate or biphenyl borate).' The fast 50% reduction can be accounted for in terms of the following mechanism (eq 9-12):
--faet
RC02H + LiBH, RC02BH3Li+ H2t 2RC02BH3Li (RC0J2BH2Li + LiBH, (RCO2I2BH2Li RCOzBH2+ RC02Li
(9) (10) (11)
faet
RCO2BH2 RCH,OB< (12) Similar reaction steps nicely account for the observations of Yoon and co-workers.' Even with 100 mol % of B-OMe-9-BBN, the reduction was not complete (Figure 3). However, 9-BBN was observed to be formed by llB NMR. It should be noted that 9-BBN reduction of acids is very slow.* The formation of 9-BBN could arise from the redistribution reaction
between B-OMe-9-BBN and a borane species generated in the r e a ~ t i o n . ~ We attempted to use this observation that reduction of acids is facile up to 50% to achieve the synthesis of lactones from dicarboxylic acids. However, both succinic and glutaric acids liberated 1 equiv of hydrogen per acid group without further reaction. Reduction of Carboxylic Acid Salts. Sodium acetate does not react with LiBH, in ether (Figure 3). However, in the presence of B-OMe-9-BBN (1 M), the reaction produced 9-BBN (-20%), but very little reduction of the salt occurred (-5% in 24 h) (Figure 3). Consequently, it should be possible to achieve the selective reduction of esters of carboxylic acid salts. Reduction of Tertiary Amides. Lithium borohydride does not reduce tertiary amides (Figure 4). On the other hand, in the presence of 1 M B-OMe-9-BBNJVJV-dimethylbenzamide was slowly reduced to the amide (40% in 24 h) (Figure 4) (eq 13). It should be noted that tertiary
__*
(a) Cho, B. T.; Yoon, N. M. Bull. Korean Chem. SOC.1982,3,149. (b) Nose, A.; Kudo, T. Yakugaku Zasshi 1976,96, 1401. (8) Brown, H. C.; Krishnamurthy, S.; Yoon, N. M. J. Org. Chem. 1976, (7)
41, 1778.
@!-NMe2
t LiBH4
f
CBoMe
((2, 1 ) ethor, nc,, 2 5 *C, 24 h
@
CH2NMe2
(13)
40%
(9) The disproportionation reaction of borane and Lewis acid, such as BCl,, is known. Brown, H. C.; Ravindran, N. J. Am. Chem. SOC.1976, 98, 1785. The use of borane as catalyst in such disproportionation reactions has been reported Brown, H. C.; Gupta, s. K. J. Am. Chem. SOC. 1971, 93,2801.
J. Org. Chem., Vol. 49, No. 21, 1984
Selective Reductions
3895
Table IV. Reduction of Representative Esters by Lithium Borohydride in Refluxing Ether in the Presence of B-Methoxy-9-BBN or Methyl Borate" reaction yield,b mp, "C, or bp, " C (torr) % found report ed ester catalyst product time, h 1.0 82 76-78 (15) 158 (760)'' 1-hexanol ethyl caproate (MeO)3B 0.5 97 58-60 58-60m B-MeO-9-BBN 1-octadecanoic methyl stearate 1.0 80 84-86 (15) 83 (14)23 (hydroxymethyl)cyclohexane ethyl cyclohexanecarboxylate (MeOhB 1.0 52-53 81 52-53'l 2,2-dimethylpropanol ethyl pivalate (MeOhB 115-117 115-1 laz4 1.0 90 1-adamantanecarbinol' ethyl 1-adamantanecarboxylate (MeOhB B-MeO-9-BBN benzyl alcohol 96-98 (15) 93 (10)26 2.0 81 ethyl benzoate 70-71 1.0 90 B-MeO-9-BBN 4-chlorobenzyl alcohol' 70-72m ethyl 4-chlorobenzoate 60-62 (15) 160-162 (760)% 0.5 84 1-hydroxy-3-chloropropane ethyl 3-chloropropionate (MeO)@ 0.5 78 (91)d 91-93 92-94'' B-MeO-9-BBN 4-nitrobenzyl alcohol' ethyl 4-nitrobenzoate "Ester = 20 mmol (2.0 M); LiBH, = 11 mmol (1.1 M); catalyst = 2 mmol (0.2 M). bAll of the products were fully characterized by 'H NMR. Unless otherwise stated, yields represent pure isolated products. 'Isolated by removing the solvent after the reaction, hydrolyzing the residue, filtering, washing with 3 M NaOH, and drying. dCrude yield. 100 -
0 Without
Cotolyrl
(01 C6H5CN 80
t 0 .c
i
60-
'
80
lb) CsHsCONMe2 IC) ClHsN Id) C6H5NO2 With 100%C B O M e
t
lo) G,HsN lb) CsHsNO?
.6 c
60-
'
-
8
0
s
40-
$
100%
~
-
40-
t i'
20 -
0-
I
I
0
10
Time (h)
-
20
10
24
Figure 4. Reduction of halides, nitriles, and amides by LiBH4 in ether at 25 "C in the presence of catalyst: [substrate] = 1M; [LiBH,] = 1 M. amides are reduced by n-Bu4NBH4and also by NaBH4 in the presence of TiC14.10 Reduction of Nitrile. Nitriles are inert to lithium borohydride. Use of 10 mol % B-OMe-9-BBN resulted in only 10% of reduction. However, with 100 mol % BOMe-9-BBN, benzonitrile was reduced to the amine in 5 h (Figure 4) (eq 14). The reaction required 8 h for com-
20
Time (h)
30
Figure 5. Reduction of sulfur containing compounds of LiBH4 in ether at 25 O C in the presence of catalyst [substrate] = 1 M; [LiBH4] = 1M.
Reduction of Sulfur Compounds. Sulfides, sulfoxides, and sulfones precipitate lithium borohydride from the ether solution, but are not reduced, even in the presence of the catalyst (Figure 5 ) . On the other hand, tosylates undergo rapid reduction with LiBH4. Thus, n-octyl tosylate is reduced in 2 h at 25 "C, producing n-octane (Figure 5) (eq 15). The reacCH3(CH2)6CH20Ts+ LiBH, EE, 25 O C , 2 h b CH3(CH2)6CH3 + LiOTs + '/2BzH6 (15) tion, followed by llB NMR, indicated the formation of BzH7-,with a broad peak around 6 -26." When the reaction was complete, llB NMR showed a broad peak at 6 17, which corresponds to B2HP This indicates that the complex [B2Hf]Li+may be stable in the presence of excess LiBH,, but decomposes to the reactants as the LiBH4 is utilized.12 Thus,the reduction of tosylates by LiBH, could be accounted for by the following reactions (eq 16-18): ROTS + 2LiBH4 RH + LiOTs + LiB2H7 (16)
-
pletion when trimethyl borate was used as the catalyst. The use of 1 equiv of catalyst was necessary since the intermediate produced should coordinate with the Lewis acid to form a relatively stable complex. Nitriles are also reported to be reduced by tetra-n-butylammonium borohydride.1° Reduction of Pyridine. Pyridine is not affected by lithium borohydride, both in the presence and absence of catalyst (Figure 4). (10) Wakamatsu, T.; Inaki, H.;Ozawa, A.; Watanabe, M.; Ban, Y. Heterocycles 1980,14, 1437. Kano, S.; Tanaka, Y.;Sugiro, E.; Hibino,
S. Synthesis 1980,695.
-.
LiB2H7
LiBH4 + BH3
2BH3
-
B2H,
(17) (18)
(11)Brown, H. C.;Tierney, P. A. J. Am. Chem. SOC.1958, BO, 1552. Gaines, D. F. Znorg. Chem. 1963, 2, 523. (12) Brown, H. C.; Stehle, P. F.; Tierney, P. A. J. Am. Chem. SOC. 1957, 79,2020.
3896 J. Org. Chem., Vol. 49, No. 21, 1984
Brown and Narasimhan
In the presence of 10 mol 7% of B-OMe-9-BBN, the reduction was complete in 1 h, a modest catalytic effect (Figure 5). As expected, 9-BBN was observed in the product. Similarly, when trimethyl borate was used, llB NMR showed the presence of (Me0)2BH (24 ppm) and MeOBHz (31 ppm), formed by the redistribution reaction with BH3. Interestingly, the these cases, B2Hf formation was not observed. Synthetic Applications. From the present study, it is evident that the enhanced reactivity of lithium borohydride in the presence of the catalyst is more promising for the reduction of esters than for other functional groups. Accordingly, we studied the reduction of a number of esters (Table IV). Utilizing stoichiometric quantities of the reagent, a long chain ester, methyl stearate, was reduced in 0.5 h (eq 19). CH3(CH,),,COOCH3
( 1 I € E , 3 5 *C, 0 . 5 h
t LiBH4 t
( 2 1 3 N NaOH
B-OMe-9-BBN can be removed from the reaction product in ether solution by a simple wash with 3 M aqueous NaOH. The catalyst evidently dissolves in aqueous sodium hydroxide as the "ate" complex (eq 20). @Me
t
NaOH t H20
-
OH
+
Na*o-'
MeOH
the alkoxy substituent. Consequently, it is appropriate to consider the mechanism of such reductions as corresponding in features to those involved in the reduction of the carbonyl groups of simple aldehydes and ketones. Three different transition states have been proposed for the reaction of borohydride with the carbonyl group of aldehydes and ketones: linear transition stateI4 (2),
2
four-center transition state15 (31, and six-center transition state16(4). However, Wigfield and Gowlandl' have ruled out 3 and 4 and have supported a modified linear transition state for the reduction of the carbonyl group by borohydride ion in protic solvents (5). On this basis, the
R 5
uncatalyzed reduction of esters presumably involves the linear transition state, 1.
(20)
n \
iiJ
'OH
Even sterically hindered esters are reduced very easily. In the absence of the catalyst, the reduction required 5 h for completion2 (eq 21). COOEt
LiBH4
+
(MeO),B
o.lk_ CICH,CH2CH20H (22)
COOEt
CH20H
I
O.Sh
I
I
R'O
R'O
In the Wigfield mechanism for the reduction of ketones, the transfer of hydride via the linear transition state 1 is assisted by a solvent molecule, 2-propanol." Similarly,we are suggesting that in the ester reduction the presence of alkene likewise helps the transfer of hydride from the borohydride ion by facilitating the departure of the borane moiety (6) (eq 24). 0
II R-c
t BH~-
+
R~-CCH=CH~
-
No2
91%
The above study suggests that the reduction of esters can be readily achieved by lithium borohydride in the presence of catalysts such as B-OMe-9-BBN and trimethylborate. It is also evident that the presence of many substituent groups can be tolerated. However, the presence of a few functional groups, such as epoxide, carboxylic acid, and tosylate, might cause difficulties with such selective reduction by undergoing concurrent reduction. Mechanism of Catalyzed Ester Reductions. (a) Catalysis by Alkenes and Amines. Considerable work has been done on the reduction of aldehydes and ketones by alkali metal borohydride^.'^ Esters can be considered to be derivatives containing a carbonyl group deactivated by resonance interactions of the carbonyl carbon atom with (13)Brown, H. C.; Krishnamurthy, S. Tettahedron 1979,35, 567.
V---C,HR2
0'-
li
a-I
1
6
I;
R-C---H---8---CH R'O
2
-
products (24)
(23)
10% NO2
a-
or R-C---H---BHs 1
I R'O
I t LiBH4 t G B O M e
1;
BH3
1
90%
+
Om-
-
CH20H
Selective reduction of esters could be achieved in the presence of groups such as chloro and nitro (eq 22 and 23). CICH&H2C02Et
4
3
Similarly, the reaction catalyzed by amines, such as pyridine, likewise is facilitated by the combination of the amine with borane (7) (eq 25).
R-C
II
I Et0
+
BH4-
+
Py
-
$?Ii
a-
R-C---H---BH,---Py
I
-
products (25)
Et0 7
(b) Catalysis by Boron Acids. Earlier, we had suggested that the catalytic effect of boron acids on the reduction of esters by BH4- involves the intermediate for(14)Brown, H. C.;Wheeler, 0. H.; Ichikawa, K. Tetrahedron, 1957, I , 214. (15)Vail, 0.R.; Wheeler, D. M. S. J. Org. Chem. 1962,27, 3803. (16)House, H. 0."Modern Synthetic Reactions", 2nd ed.; W. A. Benjamin, Inc.: Massachusetts, 1972; p 52. (17)(a) Wigfield, D.C.; Gowland, F. W. Tetrahedron 1976,3373. (b) Wigfield, D.C.;Gowland, F. W. J. Org. Chem. 1977,42, 1108.
J. Org. Chem., Vol. 49, No. 21, 1984 3897
Selective Reductions mation of more reactive borohydride derivatives (eq 26 and 27). However, we subsequently observed that the reaction (26) LiBH, + BR3 == BH3 LiR3BH LiR3BH ester products (27) of n-octyl bromide with LiBH4 is not catalyzed by representative boron acids. This observation appears to rule out this proposal. It is quite possible to extend our proposed interpretation for the catalytic effect of alkenes and amines to account for the effect of boron acids, such as Et3B, (MeO),B, and B-OMe-9-BBN (8). Indeed, the fact that the redistribu-
-+
+
0 a-
(j
a-
R-.C---H.-- BH3--- BR3
I
Et0
8
tion of R3B with R',B is strongly catalyzed by H3B (or &BH moieties) supporta this view. For the redistribution reaction, catalyzed by BH, or other B-H species, dimeric diborane derivatives have been proposed as intermediates,18closely analogous to the interaction between the BH, and BR, species that we are proposing here. An alternative way of stating this would be to propose a weak association between the borohydride moiety and the borane species, facilitating the transfer of hydride. Still another interpretation would account for the catalytic effect of the Lewis acids in terms of their ability to activate the carbonyl group for nucleophilic attack by BH, by prior or concurrent coordination with the carbonyl oxygen4 (9). a-
BR 3-
d
I/
R-C---
a-
H - - - BH3
I
Et0 9
The failure of BF,.OEh to catalyze the reaction can be attributed to its rapid reaction with LiBH, to form diborane. But then we are left with a remaining puzzle. Why do Et3B, B-OMr-9-BBN, and B(OMe), strongly catalyze the reaction of LiBH, with esters, but neither diborane (from the above reaction) nor BH3-THFexert any catalytic effect? Our primary objective in the present study was the exploration of the synthetic utility of this new catalytic effect. Consequently, it is not possible at this time to arrive at definitive conclusions regarding the mechanism involved. However, it is apparent that in addition to the valuable possibilities for these catalyzed reductions in synthetic chemistry there exists in these phenomena a rich, unexplored area for mechanistic studies. Experimental Section Materials. LiBH4 (95%, Ventron) was used without further purification. All other boron reagents used in this study were prepared by using standard procedures.*9 In all cases, the purity ~~
(18) Brown, H. C. 'Hydrobration"; W. A. Benjamin, Inc.: New York, 1962; p 59. (19) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M. "Organic Syntheses vie Boranes";Wiley-Interscience: New York, 1975; 244. (20) Brown, H. C.; Subba b o , B. C. J.Am. Chem. S O ~1956, . 78,2582. (21) Beilstein 1, 431. (22) Hovorka, F.; Lenkelma, H. P.; Stanford, 5. C. J. Am. Chem. SOC. 1938, 60, 823.
1) c
was checked by IIB NMR (> 98%). Most of the organic compounds utilized in this study were commercial products of very high purity. However, they were further purified by distillation or recrystallization when necessary. Anhydrous ethyl ether (AR grade, Mallinckrodt) was stored over 5A molecular sieves and used. Tetrahydrofuran was distilled over lithium aluminum hydride under nitrogen and used immediately. All glaesware was dried thoroughly in a drying oven and cooled under a dry stream of nitrogen. All reduction experiments were carried out under a dry nitrogen atmosphere and hypodermic syringes were used to transfer the solutions. Standard lithium borohydride solution was prepared as reported elsewhere.2 Procedure for the Rate Study. The reduction of ethyl caproate by LiBH4 in ether is representative. An oven-dried, 50-mL flask containing a side arm and magnetic stirrer was cooled under nitrogen and connected to a mercury bubbler. To the flask was added LiBH4 in ether (3.3 mL, 1.51 M, 5 mmol), followed by 0.9 mL of ether. Ethyl caproate (0.82 mL, 5 "01) was injected into the flask. The resulting solution contains 1 M of each reactant. The reaction was followed by determining the concentration of residual borohydride in 0.25-mL aliquots of the reaction mixture a t various time intervals. A blank reaction was performed under identical conditions, but without addition of compound. From the difference, the number of mmol of hydride used for reduction per mmol of ester was calculated. In cases where the reaction mixture formed a precipitate, the rate was followed by conducting the experiment under identical conditions in individual flasks, hydrolyzing the entire reaction mixture to obtain the residual hydride concentration. The rates of reaction in other cases were followed in a similar manner, maintaining identical concentrations of lithium borohydride and compound. Stoichiometry of t h e 1-Decene-Catalyzed Reduction of Ethyl Caproate by LiBH,. In a typical study, 1mmol of ethyl caproate was reacted with 25 mmol of LiBH4 in the presence of 6 mmol of 1-decene. After 8 h, the reaction mixture was hydrolyzed and the hydrogen evolved was collected and measured (- 1mL, 0.01 mmol). The amount of olefin remaining was determined by lH NMR with benzene as internal standard, 3.04 mmol. In order to analyze the products, the reaction mixture was oxidized with alkaline hydrogen peroxide (30%, 1 mL). The aqueous layer was saturated with anhydrous potassium carbonate. GLC analysis of the ether layer indicated the absence of ester. 1-Decanol and 2-decanol were obtained in 92% and 8% yield, respectively. The results are presented in Table I. Catalyzed Reduction of Esters by LiBH4. The general procedure was followed using 10 mol % of the catalyst. The rate studies are presented in Tables 11 and 111. Rate of Reduction of Representative Organic Functional Groups by LiBHa in E t h e r at 25 "C. The general procedure used for the reduction of esters was followed both in the presence and absence of catalyst. In the case of carboxylic acids, the hydrogen evolved was measured by connecting the reaction flask to a gas measuring buret through a dry ice-acetone trap. Reduction of amides and nitriles was done in the presence of 100 mol % of the catalyst. The results are presented in Figures 3-5. Reduction of Methyl Stearate. In an oven-dried, 50-mL flask containing a side arm and magnetic stirrer cooled under nitrogen was added methyl stearate (5.97 g, 20 mmol), followed by LiBH, in ether (7.3 mL, 1.51 M, 11.02 mmol). The reaction mixture was heated to reflux and B-OMe-9-BBN (0.32 mL, 0.304 g, 2 mmol) was added. &r 30 min, the solvent was removed under reduced pressure (water aspirator) and hydrolyzed using 2 N H2S04(6 mL, 6 mmol). The solid was filtered, washed with 3 M NaOH ( 5 X 5 mL) and then with water, and dried. 1-Octadecanol(5.28 g) was obtained in 97% yield: mp 58-60 "C [lit.20mp 58-60 "C]. Reduction of Ethyl Pivalate. The above procedure was followed with 10 mol % of trimethyl borate (0.23 mL, 2 mmol). (23) Heins, G . S.; Adams, R. J. Am. Chem. SOC.1926,48, 2388. (24) Stetter, H.; Schwarz, M.; Hirschhorn, A. Chem. Ber. 1969, 92, 1629. (25) Chaikin, S. W.; Brown, W. G. J . Am. Chem. SOC.1949, 71, 122. (26).Henry, L. Chem. Zentralbl. 1907, 1, 1314.
J. Org. Chem. 1984,49,3898-3904
3898
After 1 h, the product was hydrolyzed (2N H$04, 6 mL, 6 mmol). The aqueous layer was saturated with anhydrous potassium carbonate and extracted with ether (4X 5 mL). Removal of ether produced 1.43 g of 2,2-dimethylpropanol, 81% yield: mp 52-53 "C [lit.21mp 52-53 "C]. The same procedure was followed for the reduction of other esters (Table IV).
Acknowledgment. We thank the U. S. Army Research Office (Durham) (Grant ARO DAAG-29-82-K-0047) for finalcial support of this study. Registry No. LiBH4, 16949-15-8; B-MeO-9-BBN, 38050-71-4; B(OMe)3, 121-43-7; CH,(CH,),C(O)OEt, 123-66-0; PhC(O)OEt, 93-89-0;(CH,),CC(O)OEt, 3938-95-2;CH3(CH2)&(0)OMe,
112-61-8; 1-AdC(O)OEt,2094-73-7; p-ClC,H,C(O)OEt, 7335-27-5; Cl(CHZ)&(O)OEt, 623-71-2;p-N02C,H,C(O)OEt, 99-77-4; CH,(CH2)60H, 111-27-3;CH3(CH2)170H, 112-92-5;(CH3)aCCHzOH, 75-84-3; l-AdCHZOH, 770-71-8; PhCHzOH, 100-51-6; P-C~C~H~CH~O 873-76-7; H, HO(CH2)3C1, 627-30-5;pNOZC~H~CHZOH, 619-73-8;CH3(CH2)7CH=CHz, 872-05-9; LiEt3BH, 22560-16-3;Li-g-BBNH, 76448-08-3;LiEt3BOMe, 81130-65-6; LiB(OMe)z-9-BBN,81095-46-7; BF,-OE&, 109-63-7; BH3.THF, 14044-65-6; n-Bu3B, 122-56-5; n-octB(OMe)2,81044(n-D~do)~B 2467-15-4; , CH3(CHZ),43-1;(PhO)3B, 1095-03-0; CH3C(0)ONa, 127-09-3; PhCN, 100-47-0;PhC02H, 142-62-1; C(0)NMez, 611-74-5; CH3(CHz)7Br,111-83-1; CH3(CHz)70Ts, 3386-35-4; Me2S, 75-18-3; Me2S0, 67-68-5; n-BuzSOz, 598-04-9; ethyl cyclohexanecarboxylate, 3289-28-9;(hydroxymethy1)cyclohexane, 100-49-2; 7-oxabicyclo[4.l.0]heptane,286-20-4.
Vinyl Sulfone Bicycloannulation of Cyclohexenones: One-Step Synthesis of Tricycle[3.2.1.02*7]octan-6-ones Robert M. Cory* and Richard M. Renneboog Department of Chemistry, University of Western Ontario, London, Ontario, Canada N6A 5B7
Receiued April 9,1984 Vinyl sulfones bicyclowulate the d-enolatea of a-cyclohexenonesin the presence of hexamethylphosphoramide in refluxing tetrahydrofuran to give tricyclo[3.2.1.02~7]octan-6-ones in a single synthetic step. In the case of 8-methylcyclohexenones this method gives higher yields than vinylphosphonium bicycloannulation, but with cu-methylcyclohexenonesthe opposite is true. The reaction is successful with both aryl vinyl sulfones and aryl isopropenyl sulfones, but the presence of electron-withdrawing para substituents on the aromatic ring was found to be disadvantageous. Based on the isolation of intermediates and side products, the mechanism of the bicycloannulation is believed to proceed via sequential conjugate addition of the enolate to the vinyl sulfone, intramolecular Michael addition, and expulsion of arene sulfinate anion with formation of the cyclopropane ring.
Efficient construction of polycyclic systems remains one of the greatest challenges of organic synthesis. As part of a program directed toward the discovery and development of new methodology for the formation of polycyclic structures in a single synthetic step from acyclic and monocyclic precursors by bicycloannulation,' we have reported a series of methods for the bicycloannulation of cycjohexenes2 and cyclohe~enones,~ providing tricyclo[3.2.1.02.7]octanesin a one-pot operation. This tricyclic ring system (1) is a salient feature of four terpene families,
n 1
namely, the ishwaranelbp4and cy~loseychellene~ sesqui(1)For the most recent previous papers in the series Bicycloannuletion
see: (a) Cory, R. M.; Ritchie, B. M. J.Chem. SOC.,Chem. Commun. 1983,
1244. (b) Cory, R. M.; Burton, L. P. J.; Chan, D. M. T.; McLaren, F. R.; Rastall, M. H.; Renneboog, R. M. Can. J. Chem., in press. (2) Cory, R. M.; Burton, L. P. J.; Pecherle, R. G. Synth. Commun. 1979, 9, 735. (3) (a) Cory, R. M.; Anderson, P. C.; McLaren, F. R.; Yamamoto, B. R. J. Chem.SOC.,Chem. Commun. 1981,73. (b) Cory, R. M.; Renneboog, R. M. J.Chem. SOC.,Chem. Commun. 1980,1081. (c) Cory, R. M.; Chan, D. M. T.; Naguib, Y. M. A.; Rastall, M. H.; qenneboog, R. M. J . Org. Chem. 1980,45,1852. (d) Cory, R. M.; Naguib, Y. M. A.; Rasmussen, M. H. J. Chem. Soc., Chem. Commun. 1979,504. (e) Cory, R. M.; Chan, D. M. T. Tetrahedron Lett. 1975, 4441. (4) Nishida, R.; Kumazawa, 2.; Agric. Bid. Chem. 1973, 37, 341. Govindachari, T. R.; Parthasarathy, P. C. Indian J. Chem. 1971, 9, 1310. Ganguly, A. K.; Gopinath, K. W.; Govindachari, T. R.; Nagarajan, K.; Pai, B. R.; Parthaaarathy, P. C. Tetrahedron 1970,26,2371. Govindachari, T. R.; Mohamed, fi. A.; Parthasarathy, P. C. Tetrahedron 1970,26,615. (5) Willcott, M. R.; Morrison, P. A.; Assercq, J.-M.; Welch, S. C.; Inners R. J. Org. Chem. 1981, 46, 4819.
Scheme I. Bicycloannulation of Cyclohexenone
2
4
Scheme 11. Vinyl Sulfone Bicycloannulation e S O 2 R
0
6
7
terpenes and the trachylobane6 and helifdvane' diterpenes, and we have applied two of our bicycloannulation reactions to the total synthesis of ishwaranelbt8and trachyloban19-oic a ~ i d . ~ ~ , ~ While recent work elsewhere has focused on the construction of the tricyclooctanesystem of these terpenes by multistep procedures terminated by carbene insertion r e a c t i o n ~ , ~our J ~ cyclohexenone bicycloannulations (6) Ferguson, G.; McCrindle, R.; Murphy, S. T.; Parvez, M. J. Chem. Res. 1982.2009. Frena. B. M.: Gonzalez. A. G.: Hernandez, M. G.; Hanson, J. R.; Hhchcock,P: B. J.Chem. Soc., Chem. Commun. 1982,594 and references therein. (7) Bohlmann, F.; Rotard, W. Liebigs Ann. Chem. 1982,1220. Bohlmann, F.; Abraham, W.-R.; Sheldrick, W. S. Phytochemistry 1980, 19, 869. Bohlmann, F.; Zdero, R.; Zeisberg, R.; Sheldrick, W. S. Phytochemistry 1979, 18, 1359. (8) Cory, R. M.; McLaren, F. R. J. Chem. SOC.,Chem. Commun. 1977, 587. (9) Niwa, H.; Ban, N.; Yamada, K. Tetrahedron Lett. 1983,24,937. Ranu, B. C.; Sarkar, M.; Chakraborti, P. C.; Ghatak, U. R. J. Chem. Soc., Perkin Trans. 1 1982, 865. Welch, S. C.; Gruber, J. M.; Chou, C.-Y.; Willcott, M. R.; Innera, R. J. Org. Chem. 1981, 46, 4817.
0022-326318411949-3898$01.50/0 0 1984 American Chemical Society
