J. Org. Chem. 1993,58,6996-7000
6996
A Novel Smiles Rearrangement Gives Access to the A-Ring Pyridine Isomers of the Nevirapine Ring System+ John R. Proudfoot,' Usha R. Patel, and Scot J. Campbell Research and Development, Boehringer Zngelheim Pharmaceuticals, Znc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877 Received June 2, 1993.
The cyclizationof N-methylamide 9 gives, along with the expected product 2, the isomericdiazepinone 3 resulting from a novel Smiles rearrangement in which an N-methylcarboxamide functions as a leaving group. The mechanism of the reaction has been proven by isolation of the intermediate 10 and by conducting the rearrangement on the model compound 13. The relative amounta of 2,3,and 10 formed from 9 are subject to some control by variation of the base and reaction temperature (Table I). This new Smiles rearrangement was applied to the synthesis of the remaining two A-ring isomers 4 and 5 of the nevirapine ring system 1 by cyclization of the thioether 16 and the sulfoxide 17. During the course of the synthetic program which led to the discovery and development of the HIV-1 reverse transcriptase (RT) inhibitor nevirapine 11i2 we were interested in obtaining the diazepinones 3-5 in order to define the optimal ring system for anti RT activity. The
Scheme I* R
R
o
ON%b CI CI
N
O
QN%
N
CIHN I
6 R-H 7 R=CH3
aC A 1
2
3
4
'
CH3
CH3 5
path II
&Nb ~ N b ' H3C.
0
H3C.
,x
0
diazepinone 2 has been previously described,2and it was in examining a modified route to this compound that we made an observationwhich allowed us to access the isomers 3-5. Previously, 2 had been obtained by cyclization of the dianion of 8 followed by N-methylation of the tricyclic product2(Scheme I). Because only monoanion formation is required, we reasoned that the N-methylamide 9 should cyclize more readily than 8 and give direct access to 2. Cyclization of 9 does indeed proceed under milder conditions (rt in THF vs pyridine under reflux for the cyclizationof 8) but an unexpected Smiles rearrangement intervenes giving access to the isomeric diazepinone 3. Here, we demonstrate the intermediacy of this Smiles rearrangement in the formation of 3, show how variation of the reaction conditions affects the product distribution,
OKey: (a) NaH,DMSO, MeI, rt; (b) EtNH2, xylene, 150 (pressure tube), overall a, b, 92%;(c) see Table I.
J. M.; Chow, G. C.; Skoog, M. T.;Wu, J. C.; Schmidt, G.; Engel, W. W.; Eberlei n, W. G.; Saboe, T. D.; Campbell, S. J.; Rosenthal, A. S.;Adams, J. J. Med. Chem. 1991,34,2231.
(3) For areview of thesmilearearrangement,see: Truce,W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99.
N
CH3
cI 'CH3 10 X=H 10a X=Li, Na, K
O C
and apply the reaction to the synthesis of the remaining two A-ring isomers, 4 and 5, of the nevirapine ring system. The N-methylamide 9 was synthesized from 62as shown in Scheme I. Cyclization of 9 (KO-t-Bu, THF, rt, 5 min) gave two isomeric tricyclic compounds. One was assigned structure 2 on the basis of a strong NOE observed from the amide methyl group to H-4 (Figure 1) and by t Dedicated to Professor Carl Djerassi on the occasion of his 70th comparison with authentic material (NMR,TLC) prepared birthday. by the dianion route above.2 The second compound Abstract published in Aduance ACS Abstracts, November 15,1993. exhibited a strong NOE from the CH2 group to H-4 and (1) Merluzzi,V. J.; Hargrave, K. D.; Labadia,M.;Grozinger, K.;Skoog, M.; Wu, J. C.; Shih, C.-K.;Eckner, K.; Hattox, S.;Adama, J.; Rosenthal, was assigned structure 3. We rationalized its formation A. S.;Faanes, R.; Eckner, R. J.; Koup, R. A.; Sullivan, J. L. Science 1990, as shown in Scheme I. A Smiles rearrangement: involving 250, 1411. attack of the 2'-nitrogen anion on the 3-position of the (2) Hargrave, K. D.; Proudfoot, J. R.; Grozinger, K. G.; Cullen, E.; Kapadia, S. R.; Patel, U. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, J.; pyridine A-ring with displacement of the carboxamide Behnke,M.L.;Klunder,J.M.;Pal,K.;Skiles,J.W.;McNeil,D.W.;Rose,
0022-326319311958-6996$04.00/0
0 1993 American Chemical Society
J. Org. Chem., Vol. 58, No.25, 1993 6997
Isomers of the Nevirapine Ring System
Scheme I11 2
15 R = C I 16 R = S-(3,B-diMe)Ph 17 R = SO-(3,B-diMe)Ph
H
18 R = S-(3,5-diMe)Ph 19 R = SO-(J,B-diMe)Ph
&CH3
'
LH5H6%
%S%
,
I .
21 R = SO-(S,BdiMe)Ph
CH3
Figure 1. NOES observed for 2-5.
Scheme IV.
Scheme 11.
11 R = H 12 R = CH3
R f
H3C' 13
17
+ 16
O
e C-
28 R s M e
14
a Key: (a) CHCUEtOAc,rt, 99%;(b)NaH, DMSO, MeI, rt, 82%; (c) EtNHa, i-PratN, xylene, 150 OC, pressure tube, 67%; (d) NaHMDS, THF, rt, 5 min, 92%.
anion' (path 11),competes with direct ring closure (path I) in the first step. Subsequent closure of the carboxamide anion onto the 2-position of ring A gives the tricyclic compound 3, isomeric with the anticipated product 2. The intermediacy of the Smiles rearrangement was proven in two ways. We synthesized the amide 13 (Scheme 11)which can only undergo the rearrangement and not the subsequent cyclization reaction. As expected, the Smiles product 14 was obtained (92% yield) on treatment with NaHMDS in THF at rt. In a separate study aimed at isolating the intermediate 10 we examined various conditions for the rearrangement reaction (Table I). Upon deprotonation of 9 with LHMDS at low temperature the reaction proceeded only through the Smiles rearrangement, and we isolated 10 in 76% yield (Table I, entry 2). Deprotonationof 10 at rt resulted in cyclization to 3 (Table I, entry 6), supporting the sequence shown in Scheme I. Interestingly, compound 2 was also isolated from this reaction indicating that the initial rearrangement is a reversible process. When NaHMDS or potassium tertbutoxide was used to deprotonate 9 increasing amounts of the normal cyclization product 2 were seen relative to products resulting from the Smiles process (3 + 10). (4) For an example of a cnrboxamide acting as a leaving group in a S m h rearrangement,me: Fukazawa, Y.; Kato, N., Ito, S. Tetrahedron Lett. 1982, 23, 437.
a
Key: (a) 3,5-dimethylthiophenol,i-PrzEtN, dioxane, rt, 98%;
(b)SnCl~2H20,acetic acid, (concdHC1,95%;(c) 2-chloronicotinoyl chloride, i-PrzEtN, EtOAc, rt, 66% ; (d) KO-t-Bu, DMSO,MeI, rt, 88%; (e) EtNH2, dioxane 140 "C, 5 h, pressure tube, 94%; (0 NdO4, MeOH/H20, rt, 17 days, 43% (recovered 16,48%).
Coordination of the counterion to the amide group may play a role in activating it toward displacement since Li > Na > K,the relative coordination abilities, follows the trend of relative amounts of rearrangement product seen. Having demonstrated the usefulness of the Smiles rearrangementin accessingthe isomer 3 we were interested in applying the same strategy to obtain the remaining two A-ring isomers 4 and 5. By analogy with Scheme I above they should be accessible from an intermediate such as 15 (Scheme111). Direct displacementof the 4-substituent of 15 would give isomer 4 while a Smiles rearrangement followed by ring closure would give isomer 5 (Scheme111). Rather than the 4-chloro derivative 15, which would correspond to the precursor 9 used in the synthesis of 2 and 3, the 4-arylthio compound 16 was chosen as the key intermediate for the following reasons: (1) the greater reactivity of the chloro substituent in the 4-positions of the pyridine ring in 15 relative to the 2-position halogen of 9 could result in normal ring closure exclusively, (2) the sulfur atom can stabilize the a-carbanion in the depiction 18 of the transition state and favor the rearrangement, (5) Kolder, C. R.; Den Hertog, H. J. Rec. Trau. Chim. 1963, 72,286.
Proudfoot et al.
6998 J. Org. Chem., Vol. 58, No. 25, 1993 Table I. Summary of Smiles Rearrangement and Cyclization Reactions base/solvent temp ("0 time 1 9 LHMDS/THF rt 30 min 2 9 LHMDS/THF -10 2h 9 (5) 3 9 NaHMDS/THF rt 30 min 4 9 NaH/xylene 155 35 min 5 9 KO-t-Bu/THF rt 5 min 9 (11) 6 10 LHMDS/THF rt 4h 7 13 NaHMDS/THF rt 5 min 14 (92) 155 5h 8 16 NaH/xylene LHMDS/toluene rt 24 h 9 16 NaHMDS/THF -20 48 h 10 16 -20 120 h 11 16 KHMDS/ toluene rt lh 12 16 KHMDS/benzene KHMDS/ benzene rt 3h 13 17 5 3h 14 17 LHMDS/THF a Isolated yields. 78% yield of a 1:l mixture of 4 and 5 by NMR. Mixture was not fractionated.
entry
product@( 5%
starting material
and (3) an examination of the effect of sulfur oxidation state on the rearrangement reaction is possible, Le., a comparison of the reactivity of 16 vs 17. The intermediate 16 was synthesizedas shown in Scheme IV starting from 4-chlor0-3-nitropyridine.~ The results of our experiments on thioether 16 are summarized in Table I (entries 8-12). We obtained 5, the product of a Smiles rearrangement followed by ring closure, in only one instance (Table I, entry 8) and as the minor product. The structures of the isomers 4 and 5 were proven unambiguously by NOE experiments (Figure 1). Various milder reaction conditions (Table I, entries 9-12) gave exclusively 4,the product of normal ring closure. None of the isomer 5 was detected in these experiments. However, we isolated intermediate 20 from these reactions and concluded that the amide anion of 20a is not sufficiently nucleophilic to displace the arylthio group under the milder conditions which favor the Smiles rearrangement. We therefore did not examine the reaction of 16 further. As the thioether 16 was not a useful precursor of 5,the sulfoxide 17,with a potentially better leaving group, was next examined. This compound, upon deprotonation with LHMDS in THF, underwent a clean rearrangement/ cyclization to give 5 in excellent yield (Table I, entry 14). Only a trace (
