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212 Klaus Banert et al. / Solvent effects in deamination reactions

Recl. Trav. Chim. Pays-Bas 105, 272-278 (1986) 0 165-05 13186109272-07S2.25

Solvent effects in deamination reactions#

Klaus Banert, Michael Bunse, Theodor Engbert, Karl-Rudolf Cassen, Apriana W. Kurnianto and Wolfgang Kirmse*

Abteilung fur Chemie der Ruhr-Universitat Bochum, Postfach 102148, 0-4630 Bochum, Bundesrepublik Deutschland (Received February 24th. 1986)

Abstract. Nitrous acid deaminations of (S)-2-butanamine, (2R,3 S)-3-methyl-2-pentanamine (8), cyclopropananmine (17) and 4,4-dimethyl-2-adamantanamine (30) have been studied in water and in a series of carboxylic acids of decreasing polarity (acetic, 3,3-dimethylbutyric, 2-ethylhexanoic acid). The stereochemistry of aqueous deaminations varies from predominant inversion to predominant retention, depending upon the structure of the substrate (steric hindrance, neighbouring-group participation, etc.). In carboxylic acid media, alcohols arise with predominant retention, i.e. by front-side attack of the “internal” nucleophile (water). Inverting displacement of nitrogen by the “external” nucleophile (carboxylic acid/carboxylate) increases with decreasing polarity of the solvent. Even cyclopropanamine yields cyclopropyl esters (2-10 %) of inverted configuration, as shown with the aid of deuterium labels. Current mechanistic concepts are modified to account for these results.

Introduction R - NH2 + HNO,

The diazotization of primary aliphatic amines is not only the oldest method known for deamination but also one of the simplest to effect. The reaction is usually carried out in water or in acetic acid with nitrous acid generated from alkali metal nitrites. The rate-determining step is apparently the formation of a nitrosamine’. Tautomerization of the nitrosamine yields a diazonium species, the rapid decom- position of which leads to products. Although the reaction has been intensely studied, the description of the transient intermediates and the mechanisms by which they afford products are still debated2. The counter-ion hypothesis advanced by Huisgen’ and elabo- rated by White2” accounts for many features of the deamination process and has won wide acceptance. Nitro- gen ejection is thought to occur from various ion pairs, e.g. (3) and (4), intervening on the reaction path from diazotic acid (2) to solvated diazonium ion (Scheme 1). An important aspect of Scheme 1 is the incorporation of both “internal” (H,O) and “external” ( X - ) nucleophiles into the products. Deaminations in acetic readily distinguish these reaction modes, leading to alcohols and acetates, respectively. Such experiments indicate that the internal nucleophile is effectively present in the product-forming steps when R is secondary alkyl, but not when R is primary alky14. On the other hand, deaminations in H,180 revealed that the extent of I6O conservation is not dependent upon structure but rather upon pH (complete equilibration of the “internal” H2I60 with “external” H,”O is observed at near neutral pH, but not in a basic en~ironment)~. Thus, the relative contributions of various carbocation-counterion pairs (5-7) are affected by the polarity of the solvent as well as by the rate of proton-mediated exchange of the internal nucleophile.

# Dedicated to Prof. dr. Th. J. de Boer on the occasion of his retirement from the chair of Organic Chemistry at the University of Amsterdam.

R-NH-NO 1 [R-N2+] solv.

2

1 3

1 4

5 6 7 \ / \ /

R -OH R-X

Scheme 1

’ J. H. Ridd, Quart. Rev. 15, 418 (1961). For reviews see:

“E. H. White and D. J. Woodcock in “The Chemistry of the Amino Group”, S. Patai, Ed., Wiley, New York, 1968, p. 440;

bJ. T. Keating and P . S . Skell in “Carbonium Ions”, G. A. OIah and P. v. R. Schleyer, Eds., Wiley, New York, 1970, Vol. 2,

L. Friedman, ibid. p. 655; W. Kirmse, Angew. Chem. 88, 273 (1976); Angew. Chem., Int. Ed. Engl. 15, 251 (1976); W. Kirmse, Top. Curr. Chem. 80, 161 (1979). R. Huisgen and C. Riichardr, Liebigs Ann. Chem. 601, 1 (1956). R. M . Southam and M. C. Whiting, J. Chem. SOC. Perkin I1 597 (1982); H . Maskill and M . C. Whiting, ibid. 1462 (1976). B . Gold, A . Deshpande, W. Linder and L. Hines, J. Am. Chem. SOC. 106, 2072 (1984).

p. 573;

Recueil des Truvaux Chimiques des Puys-Bus, 10519, September 1986 273

water

acetic acid

3,3-dimethylbutyric acid

2-ethylhexanoic acid

The stereochemical consequence of ion-pair ollapse is retention of configuration. Predominant retention is observed in the deamination of many, though not all, secondary alkyl- amines2. The counter-ion hypothesis virtually disregards inverting displacements at alkanediazonium species. The well-established case of predominant (69%) inversion of configuration with optically active ( I-’H)-l-butanamine6 has been attributed to “the longer lifetime of a primary alkanediazonium ion and to the relative lack of steric interactions”2a. We report below that inverting displacements are more common than originally believed, and that they are accentuated in weakly polar solvents. In order to assess the effect of solvent polarity, a comparison of deaminations in water and in acetic acid is inappropriate since acetic acid (N 2.057, ET(30) 51.8 kcal/mo18) is less nucleophilic and less polar than water ( N - 0.267, ET(30) 63.1 kcal/mo19), i.e., two important parameters vary simultaneously. We there- fore used carboxylic acids with large alkyl groups, such as 3,3-dimethylbutyric acid and 2-ethylhexanoic acid [ET(30) 42.3 kcal/mo18], in order to decrease the polarity while maintaining the nucleophilicity of acetic acid. Our interest in solvent effects was stimulated by an investi- gation of 2-norbornanediazonium ions”. We found that the yield of (optically pure) endo esters from the deamination of em-2-norbornanamine increased with decreasing polarity of the solvent (Table I). This result is incompatible with a recombination of carbocation-carboxylate ion pairs but is readily explained in terms of SN2-type displacement of nitrogen. trans-4-tert-Butylcyclohexanamine showed even stronger solvent effects (Table I). The present paper extends our earlier studies to a variety of acyclic and cyclic amines.

-+ exolendo-OR + trans/cis-OR

99.910.1 9713

98.411.6 77/23

92.217.8 53/47

88.911 1.1 47/53

Results

(S)-2-Butannmine

Previous work on the nitrous acid deamination of optically active 2-butanamine in water”,’’ and in acetic acid”*I3 relied upon optical rotations; in the latter reaction, only 2-butyl acetate was investigated. We estimated enantiomeric

purities by GC of the N-(trifluoroacety1)-(S)-propyl (TFAP) amidesI4 and esters, respectively. The product mixtures obtained from deaminations in acetic acid and 2-ethylhexanoic acid were separated by HPLC, and the enantiomeric excess (e.e.) of both alcohol and ester fractions was determined (Table 11). The available literature values are in reasonable agreement with our data (all figures refer to net retention and inversion, respectively). Neighbouring-group participation is virtually absent in the 2-butyl system. From the aqueous deamination of (2-’H)- butanamine, we obtained 92% of (2-’H)-2-butanol and 8% of (3-’H)-2-butanol. The small amount of hydride shift excludes a significant contribution of hydrogen-bridged ions. Products must then arise from open 2-butyl cations or directly from 2-butanediazonium ions. In carboxylic acids, the “internal” product (alcohol) is formed with predominant retention and the “external” product (ester) with predominant inversion. Replacing water with acetic acid does not strongly affect the stereochemistry of “external” substitution. As pointed out above, this is due to the simul- taneous decrease in polarity and nucleophilicity. In 2-ethylhexanoic acid, however, the fraction of inverted ester almost doubles as compared to acetic acid. It appears that weakly

A . Streitwieser, Jr. and W . D. Schaeffer, J. Am. Chem. SOC. 79, 2888 (1957).

’ T. W.‘Bentley, F. L . Schadt and P. v. R. Schleyer, J. Am. Chem. SOC. 94, 993 (1972). Y. Marcus, E.‘Prosi and J. Hormadaly, J. Phys. Chem. 84, 2708 (1980). C. Reichardt, Angew. Chem. 91, 119 (1979); Angew. Chem., Int. Ed. Ennl. 18, 98 (1979).

l o W . Kirmse and R. Siegried, J. Am. Chem. SOC. 105, 950 (1983). ‘ I K . B. Wiberg, Ph.D. Thesis, Columbia University, New York,

’* R. A . Moss and S . M. Lane, J. Am. Chem. SOC. 89, 5655 (1967). l 3 A . B. Kyte, R. Jones-Parry and D. Whittaker, J. Chem. SOC.,

1950.

Chem. Commun. 74 (1982).

Table I Deaminations of exo-2-norbornanamine and trans-4-tert-butylcyclohexanamine.

Table 11 Deaminations of (S) ( + )-2-butanamine.

Solvent

water

acetic acid

2-ethylhexanic acid

Product ratio R-OH/R-OCOR’

18/82

16/84

Stereochemistry

ROH

22% inv.” 23% inv.” 25% inv.

51% ret.

36% ret.

ROCOR’

28% inv.” 32% inv.13 30% inv.

53% inv.

274

polar solvents enhance inverting displacement more strongly than ion-pair collapse.

Klaus Banert et al. / Solvent effects in deamination reactions

Table IV Enantiomeric excess (e.e., %) of (R)-2-methyl-3-pentyI derivatives (14) from (2R,3S)-8.

Solvent

wateP

acetic acid 3,3-dimethylbutyric acid


(2 R,3 S)-3-Methyl-t-pentanamine (8) The aqueous deamination of 8 has been studied previ- o ~ s l y ’ ~ . In contrast to the 2-butyl case, rearrangements abound in the 3-methyl-2-pentyl system. Hydrogen and methyl shifts lead to 3-methyl-3-pentanol(11) and 2-methyl- -3-pentanol (14), respectively. The 8 -, 14 transformation is associated with virtually complete inversion at C-3. There- fore 14 is thought to arise from the methyl-bridged ion 12. A degenerate ethyl shift accounts for 27% of 10, as established by means of a deuterium label (Le., the contribution of an ethyl-bridged ion to the formation of 10 may be as high as 54%)15.

Alcohols (R = H) Esters (R = COR’)

10 11 14 10 11 14

50.5 34.3 15.2

25.3 4.4 1.3 54.5 10.1 4.4

18.0 1.5 0.5 74.7 3.5 1.8

15.6 1.0 0.4 79.0 2.7 1.3

8

-/

11

Solvent

water”

acetic acid

3,3-dimethylbutyric acid 2-ethylhexanoic acid

14-OH

98.2 96

83

76

14-OCOR’ -4 84 73

73

Various intermediates contributing to the formation of 10 are shown in Scheme 3 (12 has been omitted for the sake of clarity). Configurational changes at C-2 occur by inverting displacement at the diazonium ion 9 and (in part) by intervention of the open cation 16. The bridged ion c-15 leads to racemization at both C-2 and C-3. The 2R,3R configuration of 10 is thought to arise via comer-to-corner proton shifts of c-15 or t-15 which produce the enantiomeric ethyl-bridged ion t-15’. This mechanism is supported by the relocation of deuterium labels”. Carboxylic acid solvents lower the fractions of (2S,3R)-10 and (2R,3S)-10, i.e. the amount of ethyl migration and the contribution of ethyl-bridged ions

9 10 .‘ I-% ,/’

CH3 H H..,,,::-; H T H + . P 3 R:$ ..a‘%

+ CH3 H p*,,,[:>, - - +OR-- H CH3 CH3 n H A

--c 7

H

Scheme 2 9

Variation of the solvent strongly affects the distribution and stereochemistry of the products. Rearrangements decrease with decreasing polarity of the solvent; on the other hand, the fraction of 10 increases from 50% in water to 95% in 2-ethylhexanoic acid (Table 111). Although inversion at the origin of the methyl migration remains predominant, the enantiomeric purity of 14 decreases (Table IV). A similar effect has been achieved by micellation of 8 (as the ammonium salt)I5, the micellar phase being less polar than waterI6. Partial racemization of 14 may be attributed to enhanced intervention of the open 2-methyl-3-pentyl cation (13). This interpretation is in conflict with the idea that solvation should stabilize open ions much better than bridged ions”.

16 t-15’

C-15 (2s. 3R) -10

Scheme 3

l4 B. Hakern and J. W. Westley, Chem. Commun. 34 (1966); W. Pereira and B. Halpem, Aust. J. Chem. 25, 667 (1972); R. H. Evans and J. F. Blount, J. Am. Chem. SOC. 99, 6957 (1977). W. Kirmse and E. C. Prolingheuer, Chem. Ber. 113, 104 (1980).

l6 For reviews, see: E. H. Cordes, “Reaction Kinetics in Micelles”, Plenum Press, N.Y. 1973; E. J. Fendler and J. H. Fendler, “Catalysis in Micellar and Macromolecular Systems”, Academic Press, N.Y., 1975; L. R. Fisher and D. G. Oakenfuil, Chem. SOC. Rev. 6, 25 (1977); B. Lindman and H. Wennerstrom, Top Curr. Chem. 87, 1 (1980).

l7 W. L. Jorgenson, J. Am. Chem. SOC. 99,280,4272 (1977); W. L. Jorgenson and J. E. Munroe, Tetrahedron Lett. 581 (1977); J. Am. Chem. SOC. 100, 1 5 1 1 (1978); M . E. Cournoyer and W. L. Jorgenson, ibid. 106, 5104 (1984).

Recueil des Travaux Chimiques des Pays-Bas, 10519, September 1986 275

15 is diminished. The fractions of (2R,3S)-alcohol and of (2S,3 S)-ester increase with decreasing polarity of the solvent (Table V). As above, these effects are resonably attributed to front-side return of the “internal” nucleophile (H20) and to backside attack of the “external” nucleophile (R’C0,H).

Table V Stereoisomers of 3-methyl-2-pentyul derivatives (10) from deaminations of (2 R, 3 S )-8 (alcohol and ester fractions normalized to

Solvent

water”

acetic acid



acetic acvid



2R,3S 2S,3S 2S,3R 2R,3R

alcohols

43.7 12.7 32.7 10.9

89.1 4.0 6.6 0.3

87.1 7.6 5.1 0.2

87.2 8.2 4.5 0.1

esters

56.7 33.8 8.3 1.2

41.8 54.5 2.6 1.1

37.8 59.6 2.4 0.2

Cyclopropanamine (17)

Nucleophilic displacement on cyclopropane derivatives is notoriously difficult. The transition states of both SN2 and SN1 reactions involve expansion of the remaining bond angles. This change is resisted in the case of small rings since it increases the angle strain. As a rule, cyclopropane derivatives avoid either type of nucleophilic substitution in favour of ring opening to allylic products”. Thus, cyclopropanediazonium ions seem well suited for the exploration of the limitations of inverting displacement of nitrogen. The nitrous acid deamination of cyclopropanamine in the presence 0s sodium bromide has been reported to give 3-5% of cyclopropyl bromide with inversion of configuration”. The formation of cyclopropanol in aqueous deaminations is difficult to assess because of its instability in acid solutions. In carboxylic acids, the stable cyclopropyl esters (18) are formed in increasing quantities as the polarity ofthe solvent decreases (Scheme 4). We explored the stereochemistry of the acetic acid deamination with the aid of trans-(2,2,3-2H)cyclopr~pananmine (t-20). trans-(2,2,3-’H)- Cyclopropanecarboxylic acid (t-24)20 (diastereomeric purity 91%) was converted into t-20 via Curtius degradation and into tran~-(2,2,3-~H)cyclopropyl acetate (2-21) via treatment with methyllithium, followed by Baeyer-Villiger oxidation of t-25. The cyclopropyl acetate isolated from the deamination of t-20 proved to be c-21 (diastereomeric purity 88%). The configurations of c-21 and t-21 were assigned on the basis of their coupling constants, J,,(trans) 3.1 Hz. The major product, ally1 acetate, was a 1/1 mixture of 2-22 (diastereomeric purity 88%, J,, 17 Hz) and 23. The loss of stereochemical integrity (3%) is slightly outside our experimental error ( & 1 %). Reversible deprotonation of cyclopropanediazonium ions to give diazocyclopropane is an eventual source of epimerization. In a control experiment, the deamination of 17 was run in AcOD [(O-’H)acetic acid]. Mass spectrometry of the cyclopropyl acetate thus obtained revealed incorporation of 0.02 D per molecule. Thus, within experimental error, both the displacement reaction and ring opening of cyclopropanediazonium ions proceed stereo- specifically.

* p-Toluenesulfonate.

17 18 19 CH3COZH 2.5%

/ f vCO2H 7.2

VYoAc D D D D D

t - 2 0 c-21 t -22 23

T

t - 2 4 t-25 1-21

Scheme 4

4.4-Dimethyl-2-adamantanamines (30)

2-Adamantyl derivatives are known to undergo inverting displacements very reluctantly, if at all. Schleyer and his collaborators reasoned that the axial hydrogens in this rigid molecule would block back-side approach of a nucleophile. Indeed, they found that 2-adamantyl tosylate* solvolyzes without participation of the solvent2’ or of azide ions”. We have chosen 4,4-dimethyl-2-adamantanamines (30) for our studies since they should immediately reveal the stereochemistry of the displacement reaction.

4,4-Dimethyl-2-adamantanone (26)23 was converted into syn-4,4-dimethyl-2-adamantanamine (s-30) by hydrogenation of the oxime 27. The epimeric amine a-30 was pre- pared from the tosylate 28 of syn-4,4-dimethyl-2-adaman- tanol ( ~ - 3 1 - 0 H ) ~ ~ . Treatment of 28 with hexadecyltributylphosphonium azideZ4 in cyclohexane (150°C, 114 h), followed by hydrogenation of the anti-azide 29, yielded a-30 (61%). The transformation of 28 into 29 indicates that inverting displacements at 2-adamantyl tosylates can be achieved with the aid of powerful nucleophiles and non- polar reaction conditions, suppressing S, 1 reactivity. The same strategy has been successful with other “reluctant” substrates, e.g. exo-2-norbornyl brosylateZ5, 1-methyl-7-nor-

Inverting displacements on cyclopropyl trifluoromethane- sulfonates have recently been achieved in hydrocarbon solvents: K . Banert, Chem. Ber. 118, 1564 (1985).

l 9 W. Kirmse and T. Engbert, Angew. Chem. 91, 240 (1979); Angew. Chem., Int. Ed. Engl. 18, 228 (1979).

2o J. B . Lambert and K . Kobayashi, J. Org. Chem. 42, 1254 (1977). 21 J. L . Fry, G . J . Lancelot, L . K . M . Lam, J . M. Harris, R. C.

Bingham, D . J . Raber, R. E. Hall and P. v. R. Schleyer, J. Am. Chem. SOC. 92, 2538 (1970); P. v . R. Schleyer, J . L . Fry, L . K . M . Lam and C. J . Lancelot, ibid. 92, 2542 (1970).

22 D . J . Raber, J . M . Harris, R. E. Hall and P. v. R. Schleyer, J. Am. Chem. SOC. 93, 4821 (1971).

23 F. Blaney, D . Faulkner, M . A . McKervey and G . Step, J. Chem. SOC. Perkin I 2697 (1972).

24 D . Landini, A . Maia and F. Montanan, J. Am. Chem. SOC. 100, 2796 (1978); D . Landini, A . Maia, F. Montanan and F. M . Pinki, J. Chem. SOC. Parkin I1 46 (1980).

25 K . Banert and W. Kirmse, J. Am. Chem. SOC. 104, 3766 (1982).

276 Klaus Banert et al. / Solvent effects in deamination reactions

bornyl trifluoromethanesulfonatez6 and cyclopropyl tri- fluoromethanesulfonate’8. The amines s-30 and a-30 were obtained with 99% diastereomeric purity by GC or by recrystallization of their hydrochlorides.

2 6 X . O 28 27 X = NOH 29

I

OR .s: 31 - 0-31.

Scheme 5

The deaminations of 30 in water proceed with predominant retention of configuration (Table VI). Predominant retention in the solvolyses of appropriate 2-adamantyl tosylate^^'.'^ has been interpreted in terms of weak cr participation. This notion is also supported by the formation of skeletally rearranged products from 2-adamantanediazonium ions and, in smaller yield, from 2-adamantyl t o ~ y l a t e ~ ~ . We observe a higher ratio of retention over inversion with 3-30 (ca. 15) than with a-30 (ca. 4) . This result may be taken to indicate greater participation of CH, (s-30) as compared with C(CH,), (a-30). In contrast to previous examples (2-butane- and 3-methyl-2-pentane- diazonium ions), carboxylic acid solvents do not accentuate the retentive formation of alcohols from 30. Such effects require that inverting displacement occurs in water - an unlike event with 2-adamantanediazonium ions. However, the weakly polar carboxylic acids are found to enhance inverting displacement by the “external” nucleophile even in the case of 30. The stereochemistry of the ester fraction changes from predominant retention to predominant inversion with decreasing polarity of the solvent (Table VI).

Table VI Product distributions (%) from deaminations of syn- and anti-4,4-dimethyl-2-adarnantanarnine (30).

Solvent

water

acetic acid



water

acetic acid

3.3-dimethylbutyric acid


Alcohols ( R = H) Esters ( R = COR’)

s-31 0-31 S-31 0-31

syn-amine (s-30)

94.6 6.4

21.3 2.0 50.9 19.8

24.3 2.2 36.0 31.5

24.5 3.2 30.0 42.3

anri-amine (a-30)

21.0 79.0

4.0 20.9 30.3 44.8

4.6 21.1 38.9 34.8

6.8 22.3 40.0 30.9

Conclusion

Solvent effects in deamination reactions appear to be more complex than originally anticipated. We have shown that carboxylic acids of graded polarity permit an improved evaluation. The following picture emerges from previous studies and from the present results. The stereochemistry of aqueous deaminations is largely determined by the structure of the substrates. Two broad categories may be distinguished: (1) In the absence of steric hindrance and neighbouring group participation, competing k, and k, processes lead to partial inversion of configuration (e.g. 2-butyl). (2) Enhanced steric congestion and alkyl bridging tend to suppress the k, process in favour of kA. The stereochemical result is partial retention (e.g. 3-methyl- -2-pentyl, 2-adamantyl) (Scheme 6).

Y H ISOH

R R

lkA 1 SOH

Scheme 6

Carboxylic acid media differentiate “internal” and “external” nucleophiles. In nitrous acid deaminations, the “internal” nucleophile is water, generated in the diazotization process. Nitrosoamide or triazene decompositions are more versatile in this respect2A. Decreasing polarity of the solvent favours front-side attack of the “internal” nucleophile via ion-pair collapse. For obvious reasons, the stereochemistry of alcohol formation in water and in carboxylic acids varies strongly with substrates of category (I). Smaller variations or none at all are seen with substrates of category (2). As to the “external” nucleophile, decreasing polarity of the solvent enhances inverting displacement (kJ , regardless of the substrate. Two factors probably contribute to this effect which has not previously received due attention. Firstly, the charge-dispersing transition state of bimolecular displacements is known to profit from low polarity3’. Secondly, the

26 W. Kirmse and J. Streu, J. Org. Chem. 50, 4187 (1985). 27 J. A . Bone, J . R. Pritt and M . C. Whiting, J. Chem. SOC. Parkin

I1 1447 (1975). J. E. Nordlander and J . E. Haky, J. Am. Chem. SOC. 103, 1518 (1981); see also: P. v. R. Schleyer in H. C. Brown, “The Non- classical Ion Problem”, Plenum Press, N.Y., 1977, p. 281.

29 H . J . Storesund and M. C. Whiting, J. Chem. SOC. Perkin I1 1452 (1975).

30 C. Reichardt, “Solvent Effects in Organic Chemistry”, Verlag Chemie, Weinheim, 1979, pp. 85-93.

Recueil des Travaux Chimiques des Pays-Bas, 10519, September 1986 277

2-H

1 .oo 1 .oo 1 .oo 1 .oo

exchange of "internal" for "external" nucleophiles in diazonium ion pairs becomes increasingly difficult. Thus, the carboxylic acid (carboxylate) assumes less frequently a favourable position for front-side approach. Qualitatively, the response of aliphatic diazonium ions to solvent polarity is similar to that of alkyl sulfonates or halides. However, as S t r e i t ~ i e s e r ~ . ~ ' has pointed out, the small activation barrier of nitrogen extrusion brings the rates of several competing processes closer together. The compressed energy scale allows for inverting displacements even at "reluctant" substrates (e .g . cyclopropyl, 2-adaman- tYl).

Low-field CH, High-field CH,

0.5 1 0.19

0.15 0.14

0.43 0.23

0.16 0.17

Experimental

Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Specific rotations were obtained on a Perkin-Elmer 141 polarimeter. 'H NMR spectra were recorded in CDCI, on Bruker WP-80, WM-250 and AM-400 instruments. High-pressure liquid chromatography (HPLC) was performed on a LDC instrument using 25 x 1.5 cm silica gel columns (Si 60, 5 pm, Macherey and Nagel). Gas chromatography (GC) was performed on a Siemens Sichromat equipped with glass capillary columns. Resolution of 2-butanamine was achieved by recrystallization of the diastereomeric salts with ( + )-tartaric acid, following a reported procedureg2. Since there is some disagreement in the literature with regard to the optical rotation of the active amine (values of [a],, ranging from + 7.48" 33 to + 8.1 34 have been reported), the e.e. of our sample (93 f 1 %) was determined using the GC method described in Ref. 14. The results shown in Table I1 are corrected to 100% e.e. of the amine. (2R,3 S)-3-Methyl-2-pentanamine was obtained from (L)-leucine using our original procedure". Prep. GC (4.5 m Carbowax + KOH, 100°C) afforded a sample of 99.8% purity and 98 1% e.e.

tran~-(2,2,3-~H)Cycloprpanamine (t-20) The diastereomeric purity of rrans-(2,2,3-2H)cyclopropanecarboxylic acid (t-24)*' was estimated by means of its ,H-decoupled 'H NMR spectrum, which displayed doublets at 6 0.91 (J 7.9 Hz) and 1.02 (J 4.4 Hz) in a 9/91 ratio (2-H). Analogous, but seriously overlapping, doublets appeared at 6 1.56 (I-H). Ethyl chloroform- ate (25.0 g, 0.22 mol) in 80 ml of acetone was added dropwise at 0°C to a solution of t-24 (15.1 g, 0.17 mol) and triethylamine (20.4 g, 0.20 mol) in acetone (155 ml) and water (30 ml). The mixture was stirred for 75 min at 0°C and then poured into 500 ml of ice-water. The mixture was extracted thoroughly with toluene (ca. 500 ml); the extracts were washed with water, dried over MgSO, and added dropwise to a distillation flask heated to 120°C (ca. 1 h). Progress of the Curtius degradation was monitored by IR [v(N3) 2125 cm- 'I. After heating for an additional 2 h, the mixture was cooled to 0°C and 100 ml of 30% aqueous hydrochloric acid was added. Vigorous stirring overnight and evaporation in vacuo left 15.3 g of a brown, viscous oil. 100 ml of 25% aqueous sodium hydroxide was added and the mixture was extracted thoroughly with toluene (ca. 100 ml). The extracts were dried over potassium carbonate and fractionally distilled to give 6.0 g of t-20 (purity 92%, yield 53%) which was further purified by using prep. GC (6 m Carbowax + KOH, 60°C). The deuterium-decoupled 'H NMR spectrum of t-20 displayed overlapping doublets (J 3.5 and 6.5 Hz) at 6 0.20 (2-H) and 6 2.20 (1-H).

(2.2, 3-2H)Cyclopropyl acetate (2 1)

To a solution of t-24 (1.78 g, 20 mmol) in anhydrous ether (70 ml) was added dropwise 30 ml of 1.4 M methyllithium in ether (OOC, argon atmosphere, ca. 1 h). After warming to room temp. (2 h), the mixture was hydrolyzed with saturated aqueous ammonium chloride (100 ml). The ethereal layer was separated and the aqueous phase extracted with ether. The combined organic phases were washed with brine and dried over MgSO,. Fractionation over a 30-cm column, packed with glass helices, followed by short- path distillation of the residue, afforded crude t-25. Baeyer-Villiger oxidation of t-25, following a reported proceduregs, yielded t-21 which was purified using prep. GC (4.5 m fluorosilicone QF, 90°C). 'H NMR (deuterium-decoupled): 60.53 d (J 3.1 Hz, 0.91 H), 0.60 ( J 6.7 Hz, 0.09 H), 1.91 s (3H), 4.0 two overlapping doublets (J 3.1 and 6.7 Hz, IH).

The 'H NMR spectrum of c-21, isolated from the acetic acid deamination of 1-20 (see below), showed reversed intensities and coupling constants of the doublets: 6 0.53 (J 6.7 Hz, 0.92 H), 0.60 (J 3.1 Hz, 0.13 H).

syn-4.4-Dimethyl-2-adamantanamine (s-30)

4,4-Dimethyl-2-adamantanone (26)23 (2.0 g, 10 mmol), hydroxyl- amine hydrochloride (1.07 g, 20 mrnol), ethanol ( 1 5 ml) and pyridine (5.3 ml) were refluxed for 3 h. Conventional work-up afforded 2.04 g (94%) of the crude oxime 2736 which was hydrogenated (room temp., atmospheric pressure, 3 d) in acetic acid (50 ml) with A d a m catalyst (PtO,, 0.10 8). After filtration, 30 ml of 15% hydrochloric acid was added and the mixture evaporated to dryness in vacuo. The residue was taken up in 100 ml of 2 N hydrochloric acid and the aqueous phase was rendered alkaline by addition of solid sodium hydroxide. Extraction with eher, drying of the extracts over potassium carbonate and evaporation in vacuo yielded 1.68 g (90.3%) of s-30 as a waxy solid, m.p. 70-74°C. The amine was purified by sublimation ( 130°C, lo-, Torr) or by prep. G C (Carbowax + KOH, 160°C). 'H NMR: S 1.05 s (3H), 1.24 s (3H), 1.3-2.5 m (14H), 3.19 m (IH). Alternatively, anhydrous hydrogen chloride was passed into an ethereal solution of s-30 to precipitate s-30. HCI. The hydrochloride was recrystallized from ethyl acetate/methanol. Anal. C,,H,,CIN calcd.: C 66.80, H 10.28, N 6.49; found: C 66.90, H 10.31, N 6.58%. GC of recovered s-30 indicated > 99% purity.

anti-4.4-Dimethyl-2-adamantanamine a-30)

Reduction of 26 with lithium aluminium hydrideZ3, followed by tosylation (pyridine, O'C, 14 d), afforded the tosylate 2837, m.p. 79-80°C, in 87% yield. The reaction of 28 (0.90 g, 2.7 mmol) with hexadecyltributylphosphonium azideZ4 (1.59 g, 3.4 mmol) in cyclohexane (15 ml) at 150°C (sealed ampoule, 114 h) was monitored by IR(Q+N,- 2000 cm-', 29 2100 cm-I). Short-path distillation in vacuo yielded a solution of 29 in cyclohexane which was immediately hydrogenated for 3 h with Adams catalyst (PtO,, 0.10 g) at room temp. and atmospheric pressure. The crude amine (93.2% a-30, 6.8% s-30) was purified to >99% a-30 by prep. GC (Carbowax + KOH, 160°C). 'H NMR: 6 1.03 s (3H), 1.08 s (3H), 1.2-2.35 m (14H), 3.34 (IH). Precipitation and recrystallization of the hydrochloride, as above, yielded a sample of 99% purity. Anal. C,,H,,CIN calcd.: C 66.80, H 10.28, N 6.49; found: C 66.73, H 10.25, N 6.38%. The configurations of s-30 and a-30 were assigned on the basis of the 6 and LIS values of their methyl groups. The remote amino group in a-30 effects little differentiation of the methyl groups. In contrast, the proximal methyl group in s-30 is appreciably deshielded by NH, and responds more strongly to the addition of Eu(fod), . The alcohols s-31-OH and a-31-OH behave analogously.

Table VII Relative lanthanide induced shijis (LlSj Eufod), , CDC13, AS ( P P N .

Substrate

s-31-OH

~ - 3 1 - 0 H

A . Streitwieser, Jr., J. Org. Chem. 22, 861 (1957).

54, 2639 (1976).

11956).

32 K . R. Kopecky, P . M. Pope and J . A . Lopez Sastre, Can. J. Chem.

33 P. Bruck, I . N. Denton and A . H. Lamberton, J. Chem. SOC. 921

34 H. E.'Smith, S. L . Cook and M. E. Warren, J. Org. Chem. 29, 2265 (1964).

I ,

3s W. D. Emmons and G. B. Lucas, J. Am. Chem. SOC. 77, 2287 (1955).

36 M. Alum, Curr. Sci. 50,761 (1981); C.A. 95,219799 (1981). This paper also reports the reduction of 27 with Raney nickel alloy to give 30 of unspecified configuration and purity.

37 D: Faulkner, M. A . McKervey, D. Lenoir, C. A . Senkler and P . v . R. Schleyer, Tetrahedron Lett. 705 (1973).

278 S . Sankararaman et al. / Photochemical nitration of methoxybenzenes

Deaminations (general procedure) Deaminations in carboxylic acids were performed with 1 mmol of .-

A solution of I mmol of the amine (or amine hydrochloride) in 30 ml of water was adjusted to pH 3.5 (glass electrode) with dilute perchloric acid. A conc. aqueous solution of sodium nitrite (0.25 g) and dilute perchloric acid were then added concurrently, maintaining a pH of 3.5. Stirring was continued for 24 h at room temperature. The solution was saturated with sodium chloride and extracted with ether. The extracts were dried over MgSO, and treated with 0.1 gof lithium aluminium hydride (1 h reflux) to remove alkyl nitrites. Excess LiAlH, was hydrolyzed; the precipitate was filtered off and washed with ether. The combined filtrate and washings were dried over MgSO,, concentrated and analyzed by GC. Where appropriate, the alcohols were isolated by prep. GC and acylated with N-(trifluoroacety1)-(S)-propyl chlorideI4 (2-butanol) or with (S)-2-acetoxypropionyl chloride15 (10,14) in order to allow estimation of their enantiomeric purities by GC.

amine (or amine hydrochloride) and 0.25 g of sodium nitrite in 2.5 ml of acid (24 h at room temp.). The reaction mixture was stirred with 100 ml of saturated aqueous NaHCO,, followed by extraction with ether. (Complete removal of 2-ethylhexanoic acid required several extractions with NaHCO,). The combined organic solutions were dried over MgSO,, concentrated and analyzed by GC. Peaks were assigned with the aid of authentic compounds; (crude) samples of the esters were obtained from the appropriate alcohols and acid chlorides. The ester and alcohol fractions (order of elution) were separated by HPLC with ether/hexane (I / ] ) . Hydrolysis of the esters with 0.5 g of potassium hydroxide in 2 ml of methanol at reflux was monitored by GC. The alcohols were recovered by partitioning between water and ether. For the estimation of enantiomeric purities, diastereomeric esters were pre- pared and analyzed by GC (as above).

Recl. Trav. Chim. Pays-Bas 105, 278-285 (1986) 0165-0513/86/09278-08$2.50

I. Photochemical nitration of methoxybenzenes from charge-transfer complexes with tetranitromethane*

S. Sankararaman and J. K. Kochi

Department of Chemistry, University of Houston, University Park, Houston, Texas 77004 (Received February 28th. 1986)

Abstract. The direct irradiation of the charge-transfer (CT) absorption band of the 1/1 electron donor-acceptor complexes of dimethoxybenzenes with tetranitromethane leads to aromatic nitration with a high quantum yield. The analogous methoxytoluenes under the same photochemical conditions are converted in equally high yields to products of aromatic trinitromethylation. This dichotomy with different methoxybenzenes (ArH) is discussed within the context ofthe common reactive intermediates derived from the CT excitation of the complex. The subsequent interactions of the geminate fragments,

i . e . , [ArH ’ , C(NO,), - , NO,], by radical-pair and ion-pair annihilation represent a unifying mechanism for the CT photochemistry leading to aromatic nitration and trinitromethylation.

Introduction

Aromatic compounds form n-complexes with a variety of electron-deficient organic compounds such as quinones, polyhalo-, polynitro- and polycyanoalkenes’.2. The formation of these electron donor-acceptor or EDA complexes is often accompanied by colors which vary according to the ioniza- tion potential (IP) of the aromatic donor and the electron affinity (E,) of the electron-deficient acceptor. Among the latter, tetranitromethane is especially interesting since it contains four equivalent nitro groups in a tetrahedral array about a single carbon atom3. Owing to its relatively high electron affinity (E , N 1.7 eV), it forms a variety of colored EDA complexes with different types of organic molecules3. Among these, aromatic molecules are known to interact with tetranitromethane (TNM) in several distinctive ways. On one hand, TNM forms stable EDA complexes with simple ben- zenoid hydrocarbons, as judged by the appearance of per- sistent colors upon mixing4*’. By contrast electron-rich aromatic hydrocarbons undergo aromatic substitution such as the spontaneous thermal conversion of naphthalene to 1-nitronaphthalene by TNM’. Similarly the nitration of azulene derivatives proceeds in high yields with TNM in methanol solutions containing some pyridine’. The latter also relate to the efficient nitration of cresol and N,N’-dimethyl- toluidine, the substitution patterns of which are reminiscent

of the orientations obtained in electrophilic aromatic nitration with nitric acid and derivatives”. These two types of TNM interactions with aromatic compounds may be related. Thus the formation of EDA complexes generally requires little or no activation energy’s3, and the 1/1 complex can be a direct intermediate in the thermal nitration, e .g . :

* Dedicated to Professor Thymen J. de Boer for his pioneering contributions to the organic chemistry of cations and radicals. R. Foster, “Organic Charge Transfer Complexes”, Academic Press, New York, 1969. ‘ L . J . Andrews and R . M. Keejer, “Molecular Complexes in Organic Chemistry”, Holden-Day, San Francisco, 1964. K . V. Altukhov and V. V. Perekalin, Russ. Chem. Revs. 45, 1052 (1976). I . Ostromyslensky, J. Prakt. Chem. 84, 1495 (191 1). S. Skraup and L . Freundlich, Annalen 431, 243 (1923). M. S. Newman, J . R. LeBlanc, H. A . Karnes and G. Axelrod, J. Am. Chem. SOC. 86, 868 (1964).

L . Hammick and R . B . M . Yule, J. Chem. SOC. 1539 (1940). 7aD. bT. T. Davies and D. L. Hammick, J. Chem. SOC. 763 (1938). J. N. Chaudhuri and J . Basu, J. Chem. SOC. 3085 (1959). K . Hafner and K . L. Moritz, Annalen 656, 44 (1962). A . G . Anderson, R. Scotoni, E. J . Cowles and C. G . Fritz, J. Org. Chem. 22, 1193 (1957).

IoaE. Schmidt and H . Fischer, Chem. Ber. 53, 1529 (1920). hK. Schofield, “Aromatic Nitration”, Cambridge University Press, Cambridge, 1980.