J,Org. Chem., Vol. 41, No. 14,1976
Bridging of Di-, Tri-, and Tetranitronaphthalenes Ronald B. Wetzsel for supplying several of the compounds used in this study. Special thanks are due to Dr. Lawrence Gruenke for help in obtaining various spectra. Registry No.-1, 35434-90-3; 2, 39763-54-7; 3, 40614-39-9; 4, 41809-52-3; 5, 6'76-96-0; 6, 597-50-2; 7, 100-76-5; 8, 25289-67-2; 9, 59034-21-8; 10,59034-22-9;ethanol-2,2,2-d3,1759-87-1;ethyl-2,2,2-d3 p-toluenesulfonate, 24344-87-4; ethyl-dj p-toluenesulfonate, 59034-23-0; p-toluenesulfonyl chloride, 98-59-9; ethanol-d5, 185908-1; diethyl ethyl-2,2,2-d3-phosphonate, 59034-24-1; diethyl ethylds-phosphonate, 59034-25-2. Supplementary Material Available. Two tables, one giving comprehensive listings of relative intensities of peaks observed (and, in some cases, accurately mass-measured) and another listing metastable transitions which have been observed in these studies (23 pages). Ordering information is given on any current masthead page.
References and Notes (1) A preliminary account of this work was presented at the Paclfic Conference on Chemistry and Spectroscopy,Los Angeies, Calif., Oct 1975. (2) (a)Department of Pharmaceutical Chemistry, University of California,San Francisco, Calif. (b) Department of Chemistry, University of California,
Berkeley, Calif.
2421
(3) Recipient of a Career Development Award, AM 00014, from the National
Institute of Arthritis, Metabolism and Digestive Diseases.
(4) For a review, see M. M. Bursey and M. K. Hoffman in "Mass Spectrometry,
Techniques and Applications", G. W. Milne, Ed., Wiley-lnterscience, New York, N.Y., 1971, pp 373-417.
(5)'M. Halmann and Y. Klein in "Advances in Mass Spectroscopy", Vol. 3, Elsevier, Amsterdam, 1966, p 267. (6) F. See1 and K. D. Velleman, Chem. Ber., 104, 2972 (1971). (7) Y. Kashman and E. Benary, Tetrahedron, 28, 4091 (1972). (8) R. G. Gillis and J. L. Occoclowitz in "Analytical Chemistry of Phosphorus Compounds", M. Halmann, Ed., Wiley-interscience. New York, N.Y., 1972, pp 295-331. (9) R. B. Wetzel and G. L. Kenyon, J. Am. Chem. SOC.,96, 5189 (1974). (10) R. B. Wetzel and G. L. Kenyon, J. Am. Chem. Soc., 96, 5199 (1974). (11) S. Meyerson, H. M. Grubb, and R. W. Vander b a r , J. Chem. phys., 39, 1445 (1965). (12) A. G. Harrison, E. G. Jones, S. K. Gupta, andG. P. Nagy, Can. J. Chem., 44, 1967 (1966). (13) P. Haake, R. D. Cook, and G. H. Hurst, J. Am. Chem. Soc., 89,2650 (1967). (14) F. W. McLafferty and M. C Hamming, Chem. Ind. (London), 1366 (1958). (15) C. Djerassi and C. Fenseiau, J. Am. Chem. SOC.,87, 5756 (1965). (16) A. N. H. Yeo, R. G. Cooks, and D. H. Williams, Chem. Commun., 1269 (1968). (17) F. Dagne and N. Castagnoli, Jr., J. Med. Chem., 15, 840 (1972). (18) R. G. Harvey, T. C. Meyers, H. J. Jacobson, and E. V. Jensen, J. Am. Chem. SOC., 79, 2612 (1957). (19) J. C. Craig and K. K. Purushothaman, J. Org. Chem., 35, 1721 (1970). (20) E. E. Mikhlina, V. Y. Vorobeva, S.S.Bobyleva,and L. N. Yakhontov, Khim. Farm. Zh., 15 (1969); Chem. Abstr., 72, 66779d (1970).
Meta Bridging Reactions of Electron-Deficient Aromatics. 3. Isomeric Bridging of Di-, Tri-, and Tetranitronaphthalenes to 2- and 3-Benzazocines Raymond R. Bard and Michael J. Straws* Chemistry Department, University of Vermont, Burlington, Vermont 05401 Received February 17,1976 The preparation of a series of 2- and 3-benzazocines is described which utilizes a one-step meta-bridging reaction of polynitronaphthalenes. The mode of bridging depends on the number of nitro groups in the aromatic substrate. A detailed chemical shift analysis is used to assign product structure. Evidence is presented which shows that the precursor of meta-bridged products in benzenoid systems is not a carbon bonded anionic u complex as previously reported.
We recently reported the novel meta-bridging reactions1 of electron-deficient benzenes and naphthalenes with amidines.2 The initial products of such reactions are comp l e ~ e s which ~ - ~ in certain instances undergo intramolecular cyclization to give meta-bridged products.6 The reaction is a (6,7-benzouseful synthesis of 1,5-methano-3-benzazocines morphans), potentially useful narcotic antagonist^.^,^ Several of the 3-benzazocine amidinium nitronates which we have prepared (vide infra) are long-acting narcotic antagonists in mice.g We present here a detailed product study involving reactions of deuterium labeled napthalenes which provides evidence for isomeric modes of bridging. This work allows a more definitive assignment of product structures and provides additional evidence to substantiate the way in which meta bridging occurs. Our previous work2 resulted in the isolation of only two types of adducts, 1and 3, from the reaction of amidines with sym-trinitrobenzene (TNB), 1,3-di- and 1,3,6,8-tetranitro-
R
3a (as zwitterion or salt)
+ ,'/
H
Ib
NMe,
-;'I
HiN-C,
2b
R
\
No, No; 3b (as zwitterion or salt)
la
2a
naphthalene (DNN and TETNN). When R in the starting amidine was alkyl only adducts like 1were obtained, with no evidence for cyclized products like 3. The adducts 1could not be induced to cyclize under a variety of conditions in which the amidine:aromatic ratio was varied. Interestingly, when R
2422 J.Org. Chem., Vol. 41, No. 14, 1976
8 . 7 8.5
7.0
Bard and Strauss
5.6 5.4
3.3
3.6
6 (pprn)
Figure 1.
was phenyl o n l y cyclized products like 3 were obtained. We presumed that when R = phenyl the adducts 1 were precursors of 3, the aromatic side chain facilitating cyclization by acidification of Ha.
I
I
NO2 NO2 The results presented here are concerned with a-phenoxy-N,N-dimethylacetamidine, which reacts more slowly than the a-phenyl analogues, aromatics of intermediate reactivity, 1,3,6-tri- and 1,3,8-trinitronaphthalene(TNN), as well as 1-deuterated 2,4-di- and 2,4,5,7-tetranitronaphm thalenes. These experiments have allowed us to distinguish isomeric modes of addition, a dramatic change in reactivity in going from di- and tri- to tetranitronaphthalenes, and also provide indirect evidence for intermediate complexes like 2 in meta-bridging reactions of amidines. Mixing a-alkyl-N,N-dimethylacetamidinewith TNB, DNN, or TETNN in Me2SO produces solutions which instantaneously exhibit visible spectra characteristic of the carbon-bonded anionic u complexes 112-5 isolated as the final products. On the other hand, with a-phenyl-N,N-dimethylacetamidine such solutions instantaneously exhibit spectra characteristic of isolated bridged adducts like 3.2 Only with a very large excess of aromatic do such solutions show transient spectra characteristic of C-bonded complexes like 1. After attempting such reactions with many different types of a-substituted amidines we were finally able to isolate both the pure crystalline adduct 5a and the meta-bridged product 6 from a MezSO solution of a-phenoxy-N,N-dimethylacetamidine and TNB. Our intent was to study cyclization of the isolated IJ complex 5a. Addition of 2 equiv of a-phenoxy-N,N-dimethylacetamidine (4) to 1 equiv of TNB in Me2SO yields a solution with absorption maxima at 470, 510, and 570 nm. The 510-nm maximum is characteristic of the nitropropene nitronate function in 6,2,6and the 470- and 570-nm maxima are characteristic of the C-bonded complex 5a.2,4,6Workup and fil-
tration of the recrystallized product affords 6 as the a-phenoxy-N,N-dimethylacetamidiniumsalt, which can be converted to the zwitterion 3a (R = C6H50) by addition of triethylammonium chloride (see Experimental Section). Upon standing, the filtrate obtained from the workup and recrystallization of 6 deposits well-formed crystals of the addition complex 5a. The lH NMR spectrum of purified 5a is shown in Figure 1.M o s t surprisingly, all a t t e m p t s t o induce cycliz a t i o n of 5a t o 6 w i t h excess a m i d i n e in Me2SO failed, The only reasonable alternative route to 6 is through the N-bonded addition complex 5b. If in fact 5b is a precursor of 6 it is present in very low concentrations as there is no evidence
NH
It
/ + TNB
C6H,0CH2CNMe2 4
11 02Nvy NMez
'Am:
NO2
6
CH20C6H5
NO2-
5b for it in the visible or IH NMR spectra of the reaction solution. We had previously assumed that the complex lb, analogous to 5a, was the precursor of meta-bridged naphthalene adducts like 3b. If this is not the case the possibility of isomeric bridged adducts resulting from reaction of polynitronaphthalenes and amidines must be considered, since either of the ring systems
J.Org. Chem., Vol. 41, No.14,1976 2423
Bridging of Di-, Tri-, and Tetranitronaphthalenes 7 or 8 could result depending on whether initial C or N attack occurs at C-1 or C-3.
7
trinitronaphthalene 13 was prepared from 1,8-naphthalic anhydride by nitration and decarboxylation to 2,7-dinitronaphthalene, Nitration of this compound at room temperature afforded 13. The 1,3,8-trinitronaphthalene 12 was prepared
8
Attempts to isolate addition adducts and/or meta-bridged products from the reaction of polynitronaphthalenes and a-phenoxy-N,N-dimethylacetamidine failed. In ethanol reaction does not occur at a significant rate and in MezSO a complex mixture was obtained with evidence for nitrite displacement products with TETNN. In Me2SO DNN gave only a red tar which decomposed to starting materials on workup. The problem of substantiating possible isomeric addition was approached by reaction of the more reactive a-phenylN,Ndimethylacetamidine with the deuterium-labeled substrates 9, 9a, and 10. In addition polynitronaphthalenes of increasing electrophilicity 11-14 were treated with this ami-
?
D
NO2
NO2 NO,
9a
10
NO, NO,
bb..-&
D
NO,
9
NO, NO,
RCHBCN NO, NO,
11
anhydrous EtOH
Me,"
EtOH, 0 "C
Noz
No, No,
13
14
dine in both ethanol and Me2SO solutions. TNB-d3 was prepared by heating TNB in NaOD/DMF solution. The prepa-
D(99+%) NOZ
1. DMF, NaOD 2 H,SO, I
NO, NO, ration of l-deuterio-2,4-dinitronaphthalene was achieved by in molten dehalogenation of l-chloro-2,4-dinitronaphthalene deuteriobenzoic acid containing electrolytic copper dust in a procedure similar to that described for the preparation of DNN.1° Nitration of this C-1 deuterated DNN with fuming nitric acid afforded the C-1 deuterated TETNN. The 1,3,6-
c1
No,
NO,
D (80 k)
No, ko,
+
II P RCHzCOEt, C1HCl(g)O "C
-
12
NO2
by mononitration of the commercially available 1,8-dinitronaphthalene. The amidines were prepared from appropriate nitriles via the imidate salts which were treated with dimethylamine.2
NH,
NO,
12
NH,+
II
RCH,CNMe,, C1-
NH NaoMe t anhydrous MeOH
II
RCH,CNMe,
Each of the aromatics was treated with 2 equiv of amidine in MezSO or ethanol. In most instances the bicyclic adducts were isolated, purified, and analyzed correctly for 2:l adducts of amidine and aromatic. They were converted to zwitterions by addition of triethylammonium chloride. Dramatic changes in reactivity were observed in going from 11 to 14 with a complete change in the mode of bridging from 8 to 7 as the number of nitro groups on the substrates increased. A summary of the results for reactions of the naphthalenes is shown in Table I. The critical point in distinguishing the 2-benzazocines 15, 16b, and 17b from their 3-benzazocine isomers 16a, 17a,and 18 is a correct assignment of the two bridgehead protons H-1 and H-2 (Table 111). Our previous assignments for these protons were incorrect, since we based them on changes in chemical shift which occur when the salts 18a and 19 are converted to the zwitterions 18c and 21. We assumed that those protons closest to amidine functionality would shift farthest downfield on conversion of salts to zwitterions. In fact, we have been able to show from deuterated analogues and decoupling experiments (vide infra) that the bridging CHNO2 proton H-3 shifts farthest downfield (Tables I1 and 111).In addition, we previously were unable to obtain both 2-benzazocine and 3-benzazocine isomers from a single aromatic substrate. The trinitronaphthalenes which do yield both isomers have allowed a comparative spectral analysis which is quite definitive. Complete 1H NMR absorptions for the T N B salts and zwitterionic adducts with a-phenyl- and a-phenoxy-N,Ndimethylacetamidine are recorded in the Experimental Section. There is no difficulty in assigning protons except for those bonded to sp3 carbon of the bicyclic framework. Since
2424 J. Org. Chem., Vol. 41, No. 14,1976
Bard and Strauss
Table I. Reaction of Electron-Deficient Naphthalenes with a-Phenyl-N,N-dimethylacetamidine
-
AmH'
Solvent Me,SO EtOH Me,SO EtOH Me,SO EtOH Me,SO EtOH
X=Y=H X=Y=H X = H; Y = NO, X = H; Y = NO, X = NO,; Y = H X = NO,; Y = H X = Y = NO, X=Y=NO,
AmH'
15a
No reaction
17b
17a No reaction
6b 16a 18a Nitrite displacement products
Table 11. Chemical Shifts of Protons Bonded to sp3Carbon on Bicyclic Amidine-TNB Adduct# Compd
Structure
H,
H3
H,
3.96 (under CH, of AmH+)
4.83 (dd)
4.22
4.84
4.26
(SI
(SI
HI
Hi NO,
19
Me,N
,AmH+
OD
