Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3- ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3, trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4- dibromocyclohex-1-yl)-2

Synthesis of 7-Azabicyclo[2.2.1]heptane and

2-Oxa-4-azabicyclo[3.3.1]non-3-ene Derivatives by Base-Promoted

Heterocyclization of Alkyl

N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)carbamates and

N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

Elena Go´mez-Sa´nchez,*^,†Elena Soriano,^‡and Jose´ Marco-Contelles*^,†

Laboratorio de Radicales Libres, IQOG (CSIC), C/Juan de la CierVa 3, 28006-Madrid, Spain, and

Laboratorio de Resonancia Magne´tica, Instituto de InVestigaciones Biome´dicas (CSIC),

C/Arturo Duperier 4, 28029-Madrid, Spain

iqoc21@iqog.csic.es

ReceiVed May 8, 2007

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocy-

clohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides,

investigating the effect of the nitrogen protecting group and the relative configuration of the leaving

group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted

heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a

convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction

of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room

temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose

t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]-

hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the

NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11,

13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the

protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-

azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction

mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-

trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very

clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives,

respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been

carried out to rationalize the formation of the different adducts.

Introduction

epibatidine (1)¹(Scheme 1), an alkaloid isolated from the

Ecuadorian poison frog Epipedobates tricolor,²showing high

The 7-azabicyclo[2.2.1]heptane is a common structural motif

in a number of natural or non-natural products with interesting

biological and pharmacological properties. This is the case of

(1) For some selected reviews on the chemistry and biology of epibatidine

and analogues, see: (a) Carroll, F. I. Bioorg. Med. Chem Lett. 2004, 14,

1889. (b) Daly, J. W. J. Med. Chem. 2003, 46, 445. (c) Romanelli, M. N.;

Gualteri, F. Med. Res. ReV. 2003, 23, 393. (d) Broka, C. A. Med. Chem.

Res. 1994, 4, 449.

(2) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;

Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.

* To whom correspondence should be addressed. (J.M.-C.) Tel: +34

915622900. Fax: +34915644853.

^†IQOG (CSIC).

^‡Instituto de Investigaciones Biome´dicas (CSIC).

Published on Web 10/10/2007

8656

J. Org. Chem. 2007, 72, 8656-8670

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

SCHEME 1

our attention was recently caught by a dense and complete article

published by Kapferer and Vasella¹²describing the synthesis

of 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane

(2) by intramolecular ring closure of (cis-3,trans-4)- or (trans-

3,cis-4)-dibromocyclohex-1-yl-amines (II) (Scheme 1). Based

on these results, we were intrigued by the unexplored but

seemingly possible synthesis of the same target molecules (III)

by direct base-catalyzed heterocyclization on the readily avail-

able alkyl N-(cis-3,trans-4 or N-trans-3,cis-4)-dibromocyclohex-

1-yl-carbamates or amides of type (I). If successful, this protocol

would be simpler and more economic, resulting in a more

efficient way to prepare compounds of type III^11c(Scheme 1).

These molecules are well-known intermediates for the synthesis

of epibatidine or biologically active analogues.^13,14

In this paper, we describe the results that we have obtained^11c

following this strategy, on various alkyl N-(cis-3,trans-4-

dibromocyclohex-1-yl)-carbamates or N-(cis-3,trans-4-dibro-

mocyclohex-1-yl)-2,2,2-trifluoroacetamides as well as alkyl

N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates or N-(trans-

3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides. As a

result, we have noticed that the relative configuration of the

bromine as the leaving group in the cyclohexane ring as well

as the type of nitrogen protecting group determine the course

of this base-mediated heterocyclization, leading either to

7-azabicyclo[2.2.1]heptane or to 2-oxa-4-azabicyclo[3.3.1]non-

3-ene or benzooxazolone derivatives. Reaction mechanism

studies based on DFT calculations have been also carried out

in order to rationalize these results.

affinity for the nicotinic acetylcholine receptor.³Consequently,

a series of methodologies have been reported for the preparation

of 7-azabicyclo[2.2.1]heptane derivatives, mostly based on the

Diels-Alder reaction, 1,3-dipolar cycloadditions, or in the ring

contraction of tropinones.⁴

As a well-established synthetic strategy, the intramolecular

substitution of a diverse array of free trans-4-cyclohexylamines

substituted with different good leaving goups (cyclic sulfate,

bromine, epoxide, methanosulfonates)^5-7is known to provide

the desired 7-azabicyclo[2.2.1]heptane derivatives in variable

chemical yields. However, only sporadic examples have been

reported describing the base-promoted intramolecular cyclization

of related cyclohexylamines protected as the corresponding

amides or carbamates, such as trans-N-benzoyl-O-methanosul-

fonyl-4-aminocyclohexanol,⁸trans-N-tosyl-1-chloro-4-aminocy-

lohexane,⁹or trans-N-Boc-O-methanosulfonyl-4-aminocyclo-

hexanol,¹⁰for the synthesis of 7-azabicyclo[2.2.1]heptane

derivatives.

Results and Discussion

1. Synthesis of the Precursors and Heterocyclization

Reaction. 1A. The 3-cis,4-trans-Dibromocarbamates (10, 12,

14, 16, 18, and 20). Starting from commercial (()-cyclohex-

3-enecarboxylic acid (3), N-(cyclohex-3-enyl)carbamates (4-

9) (Scheme 2) were synthesized by Curtius reaction in good

yields using the appropriate alcohol (t-butyl alcohol, benzyl

alcohol, 2-chloro-5-hydroxymethylpyridine, methanol, 2-propyn-

1-ol, 2-propen-1-ol), as described.^11,12

In this context, and prompted by our current interest in the

use of cyclohex-3-enecarboxylic acid for the synthesis of

heterocycles,^11a,band particularly 7-azabicyclo[2.2.1]heptanes,^11c

(3) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40,

4169.

(4) Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179.

Next, and after bromination, compound 4 gave known major

tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10)¹²

(50%) and minor tert-butyl N-(trans-3,cis-4-dibromocyclohex-

1-yl)carbamate (11)¹²(38%) (Scheme 2). Similarly, compounds

5-9 provided the expected mixture of epimeric 3,4-dibromides

which were readily separated and isolated by column chroma-

tography to give pure 3-cis,4-trans- and 3-trans,4-cis-dibro-

mocarbamates 12, 14, 16, 18, 20 and 13, 15, 17, 19, 21,

respectively.¹¹

After some experimentation [(a) K₂CO₃in dry acetone; (b)

NaH in THF followed by treatment with Bu₄NI; (c) Bu₄NBr,

in methylene chloride at 0 °C followed by treatment with 50%

NaOH, (d) t-BuOK in dry THF at -78 °C^15,9b], we found that

(5) (a) Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;

Zanirato, V. Tetrahedron 1997, 53, 17177. (b) Trost, B. M.; Cook, G. R.

Tetrahedron Lett. 1996, 37, 7485. (c) Sirisoma, N. S.; Johnson, C. R.

Tetrahedron Lett. 1998, 39, 2059. (d) Szantay, C.; Kardos-Balogh, Z.;

Moldvai, I.; Szantay, J.; Temesvari-Major, C. E.; Blasko, G. Tetrahedron

1996, 52, 11053. (e) Ko, S. Y.; Lerpiniere, J.; Linney, I. D.; Wrigglesworth,

R. J. Chem. Soc., Chem. Commun. 1994, 1775. (f) Barros, M. T.; Maycock,

C. D.; Ventura, M. R. Tetrahedron Lett. 1999, 40, 557. (g) Aggarwal, V.

K.; Olofsson, B. Angew. Chem., Int. Ed. 2005, 44, 5516. (h) Kosugi, H.;

Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun. 1997, 1857. (i)

Nakashima, H.; Hiroya, K.; Taniguchi, T.; Ogasawara, K. Synlett 1999,

1405. (j) Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans.

1 1999, 1253.

(6) (a) Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org. Lett. 2001, 3,

3009. (b) Lee, C.-L. K.; Loh, T.-P. Org. Lett. 2005, 7, 2965. (c) Aoyagi,

S.; Tanaka, R.; Naruse, M.; Kibayashi, C. J. Org. Chem. 1998, 63, 8397.

(7) (a) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.; Hobbs,

S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J. Org. Chem.

1994, 59, 1771. (b) Pfister, J. R.; Wymann, W. E.; Weissberg, R. M.;

Strosberg, A. M. J. Pharm. Sci. 1985, 74, 208. (c) Ramanaiah, K. C. V.;

Zhu, N.; Klein-Stevens, C.; Trudell, M. L. Org. Lett. 1999, 1, 1439.

(8) (a) Olivo, H. F.; Hemenway, M. S. J. Org. Chem. 1999, 64, 8968.

(b) Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M. Tetrahedron

Lett. 1995, 36, 7123. (c) Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina,

J. M. Synthesis 1998, 1335. (d) Avenoza, A.; Cativiela, C.; Busto, J. H.;

Ferna´ndez-Recio, M. A.; Peregrina, J. M. Tetrahedron 2001, 57, 545.

(9) (a) Palmgren, A.; Larsson, A. L. E.; Ba¨ckwall, J.-E. J. Org. Chem.

1999, 64, 836. (b) Cabanal-Duvillard, I.; Berrein, J.-F.; Royer, J.; Husson,

H.-P. Tetrahedron Lett. 1998, 39, 5181.

(11) (a) Go´mez-Sa´nchez, E.; Marco-Contelles, J. Tetrahedron 2005, 61,

1207. (b) Go´mez-Sa´nchez, E.; Marco-Contelles, J. J. Heterocycl. Chem.

2006, 43, 1455. (c) Go´mez-Sa´nchez, E.; Marco-Contelles, J. Lett. Org.

Chem. 2006, 3, 827.

(12) Kapferer, P.; Vasella, A. HelV. Chim. Acta 2004, 87, 2764.

(13) (a) Che, C.; Petit, G.; Kotzyba-Hibert, F.; Bertrand, S.; Bertrand,

D.; Grutter, T.; Goeldner, M. Bioorg. Med. Chem. Lett. 2003, 13, 1001. (b)

Wei, Z.-L.; Petukhov, P. A.; Xiao, Y.; Tu¨ckmantel, W.; George, C.; Kellar,

K. J.; Kozikowski, A. P. J. Med. Chem. 2003, 46, 921. (c) Carroll, F. I.;

Lee, J. R.; Navarro, H. A.; Ma, W.; Brieaddy, L. E.; Abraham, P.; Damaj,

M. I.; Martin, B. R. J. Med. Chem. 2002, 45, 4755.

(10) Tachihara,T.; Watanabe, H.; Kitahara, T. Heterocycles 2002, 57,

781.

(14) Dolci, L.; Dolle, F.; Valette, H.; Vaufrey, F.; Fuseau, C.; Bottlaender,

M.; Crouzel, C. Bioorg. Med. Chem. 1999, 7, 467.

J. Org. Chem, Vol. 72, No. 23, 2007 8657

Go´mez-Sa´nchez et al.

SCHEME 2

SCHEME 4

SCHEME 5

SCHEME 3

carbon of the alkyne. In fact, this reactivity was not surprising,

as a similar type of transformation has been reported using other

bases (t-BuOK, Et₃N)^17a,bor transition-metal catalysts (AuCl)^17c

but shows a particular functional limitation regarding the

generality of the present methodology for the synthesis of 7-aza-

bicylo[2.2.1]heptanes. Compound 27 slowly isomerizes to

4-methyloxazol-2(3H)-one 28 (Scheme 4) on standing at 5-

20 °C.

exo-2-Bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]-

heptane (2) was the expected compound after the NaH-DMF-

promoted heterocyclization reaction of precursor 10. Its structure

has been confirmed by simple chemical manipulation and

correlation with known compounds. As shown, acid hydrolysis

of compound 2 gave the known free amine 29,¹²which without

isolation was acetylated to provide acetamide 30 in 76% overall

yield (Scheme 5). In addition, the reaction of bromide 2 with

t-BuOK in THF rendered product 31^12,14in 78% yield (Scheme

5). This 7-azanorbornene is an intermediate in the synthesis of

epibatidine (1)^13aand epibatidine analogues^13b,cby Heck-type

reactions with conveniently functionalized substrates; conse-

quently, our new synthesis of compound 31 represents a new

formal total synthesis of epibatidine. Similar treatment of

compound 25 with t-BuOK in THF gave 7-carbomethoxy-7-

azabicyclo[2.2.1]hept-2-ene (32) (Scheme 5), an intermediate

that has also been converted in a number of epibatidine

analogues.^18aCompound 32 has been previously prepared by

Diels-Alder reaction of N-carbomethoxypyrrole and phenyl

vinyl sulfone at high pressure, followed by desulfonation, in

the reaction of 3-cis,4-trans-dibromo isomer 10 with sodium

hydride in DMF, at room temperature (rt), gave the best results,

affording 2-bromo-7-[(alkyloxy)carbonyl]-7-azabicyclo[2.2.1]-

heptane (2)¹²(52%) and 3a,4,5,7a-tetrahydro-2(3H)-benzoox-

azolone (22)¹⁶(25%) (Scheme 3) in moderate total yield, but

free of any azetidine resulting from the heterocyclization on

C-3.^12,15For comparative purposes, it is interesting to note that

compound 2 has been prepared¹²from intermediate 10 in 83%

yield, in three steps using long reaction times, while we have

demonstrated that this synthetic operation is possible in one step

only, in mild reaction conditions, and convenient chemical yield.

Very gratifyingly, carbamates 12, 14, 16, and 18, under the

same experimental conditions, afforded only the expected

7-azabicyclo derivatives 23-26 (Scheme 3) cleanly and in good

yield.

The NaH/DMF reaction of prop-2′-yn-1′-yl N-(3-cis,4-trans-

dibromocyclohex-1-yl)carbamate (20) afforded 4-methylidene-

2-oxazolidinone 27 (Scheme 4) as the result of the base-

promoted formal 5-exo-dig heterocyclization onto the internal

(15) Corey, E. J.; Loh, T.-P.; AchyuthaRao, S.; Daley, D. C.; Sarshar,

S. J. Org. Chem. 1993, 58, 5600.

(17) (a) Kimura, M.; Kure, S.; Yoshida, Z.; Tanaka, S.; Fugami, K.;

Tamaru, Y. Tetrahedron Lett. 1990, 31, 4887. (b) Tamaru, Y.; Kimura,

M.; Tanaka, S.; Kure, S.; Yoshida, Z. Bull. Chem. Soc. Jpn. 1994, 67, 2838.

(c) Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H.-G. Synlett 2006, 3309.

(18) (a) Seerden, J.-P. G.; Tulp, M. Th. M.; Scheeren, H. W.; Kruse, C.

G. Bioorg. Med. Chem. 1998, 6, 2103 and references cited therein. (b)

Altenbach, H.-J.; Constant, D.; Martin, H.-D.; Mayer, B.; Mu¨ller, M.; Vogel,

E. Chem. Ber. 1991, 124, 791.

(16) (a) Knapp, S.; Kukkola, P. J.; Sharma, S.; Dhar, T. G. M.; Naughton,

A. B. J. J. Org. Chem. 1990, 55, 5700. (c) Bayer, A.; Hansen, L. K.; Gautun,

O. R. Tetrahedron: Asymmetry 2002, 13, 2407. (d) Compound 22 has also

been described as a key intermediate for the synthesis of epibatidine:

Cabanal-Duvillard, I.; Berrien, J.-F.; Ghosez, L.; Husson, H.-P.; Royer, J.

Tetrahedron 2000, 56, 3763.

8658 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

SCHEME 6

SCHEME 8

recovered unchanged, thus indicating that bromide 36 was not

an intermediate in the formation of cyclohexene 37.

SCHEME 7

From the results obtained in the heterocyclization of dibro-

mides 10 and 11 (Schemes 3 and 7), it was apparent that the

relative configuration at the different stereocenters was playing

a major role in the chemical outcome of the heterocyclization

reaction.

To confirm the scope and generality of these results and

investigate the possible influence of the nitrogen protecting

group, we next reacted benzyl N-(trans-3,cis-4-dibromocyclo-

hex-1-yl)carbamate (13) (Scheme 2) under our usual heterocy-

clization reaction conditions. Similarly, a complex reaction

mixture resulted, where we were able to isolate and characterize

only compounds 38 and 35 in poor yields (Scheme 8).

3-(Benzyloxy)-8-bromo-2-oxa-4-azabicyclo[3.3.1]non-3-ene (38)

is the normal heterocyclization product that results after a S_N2

intramolecular reaction between the oxygen of the benzyl

carbamate at C-1 and the bromine atom at C-3, particularly

favored due to the trans arrangement of these functional groups.

In addition to the spectroscopic analysis, the structure of

compound 35 has also been confirmed by acetylation to give

6-(benzyloxycarbonylamino)cyclohex-2-enyl acetate (39) in

64% yield (Scheme 8). Note that compound 35 is identical to

the product obtained during the carbamoylation of aminoalcohol

33 (Scheme 6) (see the Experimental Section), and to the product

reported by Bayer et al. following a different route.^16cThe

formation of benzyl 2-hydroxycyclohex-3-enylcarbamate (35)

is probably the result of a similar reaction mechanism that gives

compound 22 from the parent precursor 11 (Scheme 7) and

reflects the low stability of the presumed allylic 2-benzyloxy-

2-oxazoline intermediate to the reaction conditions.¹⁹

1C. The 3,4-Dibromo-2,2,2-trifluoroacetamides (40, 42).

It was evident that in order to have an efficient approach to

7-azabicyclo[2.2.1]heptane derivatives, the key point was the

ready availability of appropriate (3-cis-4-trans-dibromocyclohex-

1-yl)carbamate derivatives. Intermediates 10, 12, 14, 16, and

18 must be separated by chromatography from the corresponding

3-trans-4-cis-dibromo isomers (Scheme 2), always present in

the reaction medium, and afford the corresponding 7-azabicyclo-

[2.2.1]heptanes in moderate yields (52-78%) (Scheme 3). We

next considered the readily available N-(3-cis,4-trans-dibro-

mocyclohex-1-yl)-2,2,2-trifluoroacetamide, which we could

isolate in 72% yield, accompanied by minor amounts of its N-(3-

trans,4-cis-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide iso-

mer during the bromination of N-(cyclohex-3-enyl)-2,2,2-

trifluoroacetamide, as reported.¹²

29% total yield.¹⁸Our approach leads to the same compound

in a similar total yield (25%, four steps), requiring two steps

more; however, we assume that the present method is easier,

as no special experimental apparatus or device is necessary, and

more flexible, as it gives potential useful intermediates such as

25 (Scheme 3). Another advantage is that the starting materials

are less expensive. As a further comparison, an alternative

method from N-carbomethoxypyrrole^18abut not relying in a

high-pressure step, provides 32 in a three-step sequence with a

mere 10% yield.

The formation of 3a,4,5,7a-tetrahydro-2(3H)-benzooxazolone

(22) in the heterocyclization of precursor 10 was totally

unexpected (Scheme 3), but the structure of this compound has

been unequivocally established by its spectroscopic data, and

by comparison with those described in the literature for the same

known product.¹⁶We have also confirmed the structure of

oxazolone 22 by chemical transformations. As shown, basic

hydrolysis gave 6-aminocyclohex-2-enol (33), whose acetylation

furnished the peracetylated derivative 34 (Scheme 6). As an

additional proof N-benzylcarbamate 35^16cwas synthesized from

intermediate 33 under the usual conditions (Scheme 6).

1B. The 3-trans,4-cis-Dibromocarbamates (11, 13). In view

of the interesting results obtained with the 3-cis,4-trans-

dibromide 10, we turned our attention to the heterocyclization

reaction of the 3-trans,4-cis-dibromide isomer 11 (Scheme 2).

Vasella et al. have reported that this compound could be

converted into the same 7-azabicyclo[2.2.1]heptane (2) (Scheme

1) in 62% overall yield, in three steps, in a time-consuming

process that involved heating the free amine at 130 °C during

2 days.¹²These conditions (K₂CO₃, 1,2-dichlorobenzene, 3 days)

applied to compound 11 yielded a complex reaction mixture,

from which we could isolate unreacted compound 11 (25%),

unsaturated carbamate 4 (15%), and 3-cis,4-trans-dibromide 10

(13%). When we submitted compound 11 to NaH/DMF, the

reaction was also complex, affording in this case compound 22

(44%) and a mixture of (1SR,5SR,8RS)-8-bromo-2-oxa-4-

azabicyclo[3.3.1]nonan-3-one (36) and (1SR,5SR)-2-oxa-4-

azabicyclo[3.3.1]non-7-en-3-one (37) in a 3.6:1 ratio, as we

could determine by GC/MS analysis (Scheme 7). After

chromatography, we were able to obtain pure samples of

compounds 36 and 37 (see the Experimental Section). Very

interestingly, when the mixture 36+37 was further treated with

NaH/DMF (or t-BuOK/THF) looking for a possible total

transformation of bromide 36 into alkene 37, the mixture was

The NaH/DMF-promoted heterocyclization reaction of N-(3-

cis,4-trans-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40)

afforded the expected 7-azabicyclo[2.2.1]heptane derivative 41

in good yield (81%) (Scheme 9). Basic hydrolysis of compound

(19) In view of the reactivity observed with 3-trans,4-cis-dibromocar-

bamates 11 and 13, similar analysis was not further investigated in related

derivatives 15, 17, 19, and 21.

J. Org. Chem, Vol. 72, No. 23, 2007 8659

Go´mez-Sa´nchez et al.

SCHEME 9

SCHEME 11. Mechanism for the Formation of Compounds

2 and 22 from Dibromide 10

SCHEME 10

41 followed by acetylation gave product 30 in 72% yield

(Scheme 9), identical in all analytical and spectroscopic data

to the compound isolated in a related synthetic sequence starting

from carbamate 2 (Scheme 5). For comparative purposes, it is

interesting to note that Vasella has described the transformation

of 2,2,2-trifluoroacetamide 40 (Scheme 9) into bromide 2 in

good overall yield (93%), but in a time-consuming three-step

synthetic sequence, as the first deprotection step required

13.5 h, the cyclization 13 days, and the reprotection 3 days,¹²

while we have been able to obtain a similar N-protected,

functionalized 7-azabicyclo[2.2.1]heptane such as 41 (Scheme

9) in one step only in 81% yield.

The clear advantage of the 2,2,2-trifluoroacetamide protecting

group as stereodirecting and amide carbanion stabilizing group

has also been observed in the base-promoted heterocyclization

of N-(3-trans,4-cis-dibromocyclohex-1-yl)-2,2,2-trifluoroacet-

amide (42). As shown in Scheme 10, treatment of this dibromide

with NaH/DMF afforded once more one compound only (43)

in 79% yield, a relatively unstable product as we have observed

that it slowly decomposes to the amino alcohol 44 (Scheme

10) on standing at 5-20 °C. The structure of bromide 43 has

been confirmed by acid hydrolysis of the dihydro-1,3-oxazine

moiety to provide 5-amino-2-bromocyclohexanol (44) as the

corresponding trifluoroacetate, which on acetylation gave

derivative 45 in 99% yield. t-BuOK/THF-promoted hydrogen

bromide elimination on compound 45 provided ketone 46²⁰in

low yield. The formation of ketone 46 is probably the result of

the preferred capture of the hydrogen bonded to the carbon

bearing the acetoxy group, located in a favorable trans-diaxial

arrangement referring to the leaving group followed by bromide

elimination, and aqueous hydrolysis of the intermediate enol

ester during the workup. The same reaction conditions applied

to bromide 43 afforded vinylic bromide 47 (Scheme 10), which

is presumably formed after the capture of the hydrogen located

in the carbon bearing the bromine atom, and double bond

formation, followed by protonation.

analytical and spectroscopic data in good agreement with their

structures, and when known, with the reported data^21-23(see

the Supporting Information).

2. Mechanisms of the Heterocyclization Reactions. In this

section, we present potential reaction mechanisms for the

formation of the products obtained on the basis of a DFT study.

We will focus on the precursor tert-butyl N-(cis-3,trans-4-

dibromocyclohex-1-yl)carbamate (10) and on its isomer 3-trans,4-

cis-dibromide (11) as models.²⁴

We describe herein the reaction energy profiles from the

reactive species A1, formed by abstraction of the carbamate

proton in 10 by the strong base.²⁵A1 may evolve through

(21) Maier, M. E.; Lapeva, T. Synlett 1998, 891.

(22) Ryan, R. J.; Julia, S. Tetrahedron 1973, 29, 3649.

(23) (a) Crossley, M. J.; Davies, S. R.; Hambley, T. W. Aust. J. Chem.

1994, 47, 2221. (b) Orlek, B. S.; Borrett, G. T.; Smith, D. M. J. Chem.

Soc., Perkin Trans. 1 1993, 1299. (c) Miyamoto, M.; Aoi, K.; Morimoto,

M.; Chujo, Y.; Saegusa, T. Macromolecules 1992, 25, 5878.

(24) For the sake of brevity, the theoretical study on related processes

(formation of 35 and 38 from 13, and 47 from 43) is shown in the Supporting

Information.

In addition to the chemical manipulation and correlations with

known compounds, all products described in this work showed

(20) Baginski, M.; Claudi, F.; Giorgioni, G.; Fontenla, J. A.; Rosa, E.;

Cardellini, M. Bioorg. Chem. 1996, 24, 358.

8660 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

FIGURE 2. Free energy profiles in solution (DMF) and DFT-optimized geometries for direct cyclizaton routes of A1.

FIGURE 3. Free energy profiles in solution (DMF) for the formation of 22.

different pathways (Scheme 11), and three direct cyclization

routes may be envisaged: (1) to the expected product 2, by

intramolecular S_N2 displacement of the trans-bromine at C4;

(2) to the bicyclo[3.2.2]nonene 50, through nucleophilic attack

of the carbamate oxygen at C4; and (3) to the bicyclo[3.1.1]-

heptane 51.

conditions, probably due to steric hindrance induced by the cis-

bromine and the strong steric strain of the forming cyclobutane

framework. Cyclization to 50 takes place with a moderate energy

barrier (25.25 kcal mol^-1) in a weakly exothermic step (-3.91

kcal mol^-1).

To summarize, the formation of 2 is kinetically and thermo-

dynamically favored over other plausible direct heterocycliza-

tions, in agreement with the experimental findings since 51 and

50 were not detected.

DFT calculations in solution²⁶(Figure 2) show that formation

of 2 is exothermic (-24.65 kcal mol^-1) and takes place with a

reasonably low free-energy barrier (16.08 kcal mol^-1). In

contrast, formation of 51 is predicted to involve a very high

barrier (45.14 kcal mol^-1), prohibitive under the experimental

The competitive formation of 22 might imply that a secondary

reaction involving elimination of the tert-butyl moiety in A1

could take place in the strong basic medium, leading to species

A2, which would then suffer a regioselective hydrogen bromide

elimination and an intramolecular S_N2′ displacement (Scheme

11, path I). This reactivity is very unusual, although it has been

described.²⁷Likewise, the Fmoc protecting group can be cleaved

(25) A scan of the potential energy surface (PES) for the system [10 +

NH₂^-] was performed (see Figure 1, Supporting Information), and the results

reveal a double-well energy profile and a barrierless pathway for the

formation of A1.

(26) The gas-phase results for the reactions evaluated are summarized

in the Supporting Information.

J. Org. Chem, Vol. 72, No. 23, 2007 8661

Go´mez-Sa´nchez et al.

SCHEME 12. Mechanism for the Formation of Compounds

22, 36, and 37 from Dibromide 11

by ammonia and simple amines like triethylamine, DBU, or

diisopropylamine,^28aand di-Boc-protected R-amino acids can

be selectively removed to give mono-Boc compounds.^28b

The hydrogen bromide elimination must take place before

the intramolecular S_N2′ displacement, but the complete sequence

of events is unknown. Thus, the fragmentation step may proceed

before or after the elimination or cyclization process. The

reductive elimination of the tert-butyl group to form A2 (Scheme

11) seems doubtful because it is a dianionic structure and likely

very high in energy. Moreover, the E₂hydrogen bromide

elimination to generate the conceivable intermediate A3 should

compete with this process. Computational results show that the

base-assisted fragmentation to A2 proceeds with an activation

barrier significantly higher than the elimination to A3 (33.67

vs 17.81 kcal mol^-1in solution, respectively). Additionally, we

were unable to locate the cyclization transition structure

connecting the intermediates A4 and A5 (path I); the reaction

evolves instead through intramolecular proton abstraction by

the carbamate, leading to diene A6. Although this result might

be attributable to computational artifacts, the strong basic

character of A4 and the proximity of functional groups may

induce an easier elimination toward A6. Hence, these findings

suggest that path I may be discarded as an operating mechanism,

and the formation of A3 is probably the first step toward the

formation of 22.

The carbamate group in A3 shows analogous electronic and

steric properties to A1, so the base-promoted extrusion of alkene

is expected to be as high in energy as from A1 to A2.

Alternatively, a deprotection via retro-ene reaction is also

plausible (Scheme 11, path II). This is not necessarily a thermal

process, and it can be accelerated at room temperature under

basic conditions.²⁹The retro-ene process of A3 generates A7

through the asymmetric transition structure TS_A7(C-H )

1.672 Å, N-H ) 1.103 Å, C-O ) 1.660 Å).³⁰This step is

highly exothermic but kinetically unfavored, as the activation

energy to reach TS_A7is very high (41.10 kcal mol^-1; see Table

2, Supporting Information). Finally, A7 would undergo an easy

intramolecular S_N2′ displacement to form 22 through TS_22II

(activation barrier of 16.78 kcal mol^-1).

The high activation barrier computed for the fragmentation

to A7 prompted us to search for alternative paths. Thus, a

mechanism where this step is the final event can be envisaged

(Scheme 11, path III). A3 may drive heterocyclization through

TS₅₂to 52 by intramolecular syn-nucleophilic attack of the

carbamate oxygen onto the cycloalkene. The barrier for this

thermoneutral cyclization is 25.6 kcal mol^-1. At this point, the

fragmentation of the alkyl chain might proceed, as proposed

above, assisted by the base or via retro-ene reaction (Scheme

11, path IV). In the first case, A5 is formed via TS_A5in a

kinetically more favored fragmentation than from A1 (barrier

of 26.39 kcal mol^-1). The alternative [1,5]sigmatropic H-shift

of 52 (Scheme 11, path IV) proceeds through a half-chair

transition structure TS_22IV. This step is thermodynamically

favored (exothermic by 20 kcal mol^-1), and the activation barrier

is moderate (24.05 kcal mol^-1). It should be noted that TS_22IV

is 2.35 kcal mol¹more stable than TS_A5, therefore supporting

path IV; however, a competition between both fragmentation

routes cannot be ruled out.

In total, these findings suggest path IV (Scheme 11) as the

putative operative mechanism: this three-step route is thermo-

dynamically feasible, involves moderate activation barriers, and

is kinetically preferred over alternative paths. The rate-limiting

step is the heterocyclization event, although the alkyl fragmenta-

tion involves a slightly lower barrier. The potential energy

surfaces computed for paths II-IV are depicted in Figure 3.

According to these results, the formation of 22, 36, and 37

in the heterocyclization of tert-butyl N-(trans-3,cis-4-dibro-

mocyclohex-1-yl)carbamate (11) (Scheme 7) could be explained

as shown in Scheme 12. The reactive anion B1, probably

because of stereochemical restrictions, does not cyclize to

compounds epi-51 or epi-2. In fact, the strong steric repulsion

between the Boc group and the cis-bromine at C4 gives rise to

(27) Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701.

(28) (a) Sua´rez-Castillo, O. R.; Montiel-Ortega, L. A.; Mele´ndez-

Rodr´ıguez, M.; Sa´nchez-Zavala, M. Tetrahedron Lett. 2007, 48, 17. (b)

Mohapatra, D. K.; Durugkar, K. A. ArkiVoc 2005, xiV, 20.

(29) Jung, M. E.; Davidov, P. Org. Lett. 2001, 3, 3025.

(30) For some DFT studies of intramolecular retro-ene reactions, see:

(a) Jabbari, A.; Sorensen, E. J.; Houk, K. N. Org. Lett. 2006, 8, 3105. (b)

Yu, Z. X.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 13825. (c) Loncharich,

R. J.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 6947.

8662 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

FIGURE 4. Free energy profiles in solution (DMF) for the direct cyclization of B1.

FIGURE 5. Free energy profiles in solution (DMF) computed for the formation of 22 and 37 from carbamate 11.

a very high activation energy for the cyclization to epi-2 (Figure

4). The steric tension involved in the N attack on C3 may

account for the high barrier in the formation of epi-51. On the

contrary, the unstrained oxygen attack to C3 justifies the low

barrier, which points to a kinetically favored, selective, formation

of the bicyclo[3.3.1]nonene epi-50.

In this context, formation of compound 36, closely related

with epi-50, might take place from this bicycle in a further retro-

ene process (Scheme 12). The transition structure (TS₃₆)

involves a moderate activation energy of 20.39 kcal mol^-1, thus

supporting this hypothesis.

Compound 37 could be formed by a hydrogen bromide

elimination from 36. However, the inspection of 36 reveals that

the pseudoequatorial orientation of the bromine should not be

favored to undergo this process, a fact that has been experi-

mentally confirmed as we could not transform 36 into 37

(Scheme 7). Although the pertinent transition structure could

be successfully located and characterized, the activation energy

was found to be high (33.61 kcal mol^-1), so we searched for

other mechanistic proposals.

On the basis of the preferred pathway computed for 10, we

might speculate that transformation of B1 into 22 follows an

analogous three-step mechanism via E₂elimination, heterocy-

clization through S_N2′ and retro-ene processes. Whereas B1

conformer (Scheme 12) is ideally functionalized to give

compound 36, the pseudoequatorial disposition of the bromine

avoids the expected elimination. Conversely, the conformer B2

displays pseudoaxial bromine disposition at C3, hence allowing

the elimination to form B3 (and finally 22, Scheme 12, path

a), and simultaneously at C4, thus giving intermediate B4,

precursor of compound 37 (Scheme 12, path b). Note that

conformer B2 is 3.35 kcal mol^-1less stable than B1.

B2 keeps the main features of the model system A1, so the

energy profile computed for the formation of 22 following path

a is parallel, and only slight energy differences are observed

(Table 3, Supporting Information).

Formation of 37 proceed through a competing elimination,

affording intermediate B4 (Scheme 12, path b). A comparison

between the energetics for path a and b reveals a kinetic and

thermodynamically favored base-assisted elimination of the

J. Org. Chem, Vol. 72, No. 23, 2007 8663

Go´mez-Sa´nchez et al.

proton at C2. The following intramolecular S_N2′ displacement

to give 53 proceeds via TS₅₃with a higher energy barrier than

that estimated for the related cyclization to epi-50, although B4,

lacking cis bromine substituent would imply a lower steric

hindrance. Finally, the alkyl chain fragmentation of 53 drives

to 37.

Experimental Section

General Methods. Melting points were determined on a Kofler-

type microscope and are uncorrected. ¹H NMR and ¹³C NMR

spectra were recorded at rt in CDCl₃, at 300, 400, or 500 MHz and

at 75, 100, or 125 MHz, respectively, using solvent peaks (CDCl₃:

7.27 (D), 77.2 (C) ppm; D₂O: 4.60 ppm) as internal reference.

The assignment of chemical shifts is based on standard NMR

experiments (¹H, ¹³C, DEPT, ¹H-¹H COSY, HMQC, HMBC). In

the NMR spectra, values with (*) can be interchanged. Mass spectra

were recorded on a LC/MS spectrometer with an API-ES ionization

source. Elemental analyses were performed at CQO (CSIC, Spain).

TLC was performed on silica F254 and detection by UV light at

254 nm or by charring with either ninhydrin, anisaldehyde, or

phosphomolybdic-H₂SO₄dyeing reagents. Where anhydrous sol-

vents were needed, they were purified following the usual proce-

dures. In particular, anhyd DMF was critical for the outcome of

the cyclization reaction and was either distilled at reduced pressure,

bought from Aldrich (99.8%), or purified through a Pure solv PS-

400-3-MD model. Column chromatography was performed on silica

gel 60 (230 mesh).

The rate-limiting step for the formation of 22 and 37 is the

heterocyclization, as for the transformation of 10 into 22. The

high activation barrier and exothermicity for the first-step

prevent the reverse process, making the product distribution

dependent on the relative activation energies of the two

competing paths a and b. Figure 5 shows the energy profiles

computed for the transformation of 11 into 22 and 37.

The formation of compounds 35 and 38 (Scheme 8) during

the base-promoted heterocyclization of 13 follows a mechanism

analogous to that discussed for the Boc-protected precursor 11,

so the interested reader is referred to the Supporting Information

for deeper details.²⁴

[(6′-Chloro-3′-pyridyl)methyl]-N-(cyclohex-3-enyl)carbam-

ate (6). Following the general procedure for the Curtius reaction

(method A), to a solution of cyclohex-3-enecarboxylic acid (3) (216

mg, 1.71 mmol) in 6 mL of dry toluene were added dropwise Et₃N

(0.26 mL, 1.88 mmol, 1.1 equiv) and DPPA (0.44 mL, 2.05 mmol,

1.2 equiv). The reaction mixture was stirred for 20 min at rt and

60 min under reflux. 6-Chloropyridine-3-methanol (196 mg, 1.37

mmol, 0.8 equiv) was then added, and the resulting mixture was

stirred under reflux for 17 h. Workup and flash chromatography

(hexane/AcOEt, 32% to AcOEt) yielded compound 6 (329 mg,

90%) as a white solid: mp 82-4 °C; IR (KBr) ν 3428, 3310, 3029,

2920, 1687, 1537, 1461, 1239, 1111, 1048 cm^-1; ¹H NMR (CDCl₃,

200 MHz) δ 8.40 (d, J ) 2.3 Hz, 1H, H2′), 7.68 (dd, J ) 2.3 and

8.1 Hz, 1H, H4′), 7.33 (d, J ) 8.1 Hz, 1H, H5′), 5.65 (m, 2H, H3,

H4), 5.09 (s, 2H, CH₂O), 4.79 (br s, 1H, NH), 3.86 (br s, 1H,

CHNH), 2.41 (d, J ) 17.2 Hz, 1H, H2A), 2.20-2.00 (m, 2H, 2H5),

2.00-1.80 (m, 2H, H2B, H6A), 1.70-1.50 (m, 1H, H6B); ¹³C

NMR (CDCl₃, 50 MHz) δ 155.0 (NHCO₂CH₂Ar), 150.7 (C3′),

149.0 (C2′), 138.4 (C4′), 131.2 (C6′), 126.6 (CHdCH, C4), 124.0

(CHdCH, C3), 123.8 (C5′), 62.6 (NHCO₂CH₂Ar), 46.2 (C1), 31.5

(C2), 28.0 (C6), 23.3 (C5); MS (ES) m/z [M + 1]⁺267.0, [M +

23]⁺289.0. Anal. Calcd for C₁₃H₁₅ClN₂O₂: C, 58.54; H, 5.67; N,

10.50. Found: C, 58.76; H, 5.57; N, 10.43.

Methyl N-(Cyclohex-3-enyl)carbamate (7). Following the

general procedure for the Curtius reaction (method A), a solution

of cyclohex-3-enecarboxylic acid (3) (258 mg, 2.05 mmol) in dry

toluene (6.4 mL, 0.32 M) was reacted with Et₃N (0.33 mL, 2.46

mmol, 1.2 equiv) and DPPA (0.46 mL, 2.15 mmol, 1.05 equiv).

After the solution was refluxed for 4 h, dry methanol (0.4 mL,

10.24 mmol, 5 equiv) and CuCl (13.6 mg, 0.14 mmol, 0.067 equiv)

were added, followed by warming at 70 °C for 4 h. Workup and

flash chromatography (hexane/AcOEt, 10%) gave carbamate 7 (243

mg, 76%) which showed spectroscopic data [¹H NMR (CDCl₃, 300

MHz) δ 5.74-5.64 (m, 1H), 5.64-5.55 (m, 1H), 4.69 (br s, 1H),

3.94-3.76 (m, 1H, HCN), 3.67 (s, 3H, OCH₃), 2.42 (m, 1H), 2.24-

2.02 (m, 2H), 1.96-1.80 (m, 2H), 1.66-1.50 (m, 1H)] identical to

those described³¹for the same compound.

3. Conclusions

In this work, we have investigated the effect of the relative

configuration as well as the influence of the nitrogen protecting

group on the base-mediated heterocyclization of (3,4-dibro-

mocyclohex-1-yl)amines. Consequently, the sodium hydride/

DMF-promoted heterocyclization of alkyl N-(cis-3,trans-4-

dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a

convenient method for the synthesis of the 7-azabicyclo[2.2.1]-

heptane derivatives. The NaH/DMF-mediated heterocyclization

of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11,

13) is a more structure-dependent reaction, giving rise to 2-oxa-

4-azabicyclo[3.3.1]non-3-ene derivatives from low to moderate

yields, in complex reaction mixtures. Conversely, the NaH/DMF

heterocyclization reactions of N-(cis-3,trans-4-dibromocyclohex-

1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibro-

mocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean,

giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]-

non-3-ene derivatives, respectively, in good yields. In summary,

the appropriate selection of the nitrogen protecting group on

the easily available 3,4-dibromocyclohex-1-yl amines allowed

us to control the type of final product obtained. As a practical

application, the reaction of tert-butyl N-(cis-3,trans-4-dibro-

mocyclohex-1-yl)carbamate (10) with sodium hydride in DMF

at room temperature provided 2-bromo-7-[(tert-butoxy)car-

bonyl]-7-azabicyclo[2.2.1]heptane (2) in 52% yield. t-BuOK-

promoted hydrogen bromide elimination in compound 2 afforded

7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in

78% yield, an intermediate in the total synthesis of epibatidine

(1) (Scheme 1).¹³

In addition, compounds of type 2 or 41 are very well

funtionalized in order to explore the synthesis of C-2 susbtituted

epibatidine analogues, by simple bromine S_N2 nucleophilic

displacements or intermolecular free radical reactions. Similarly,

2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives such as 43 have

been easily transformed into 3-aminocyclohexane derivatives

(45-47), a series of compounds of wide and potential synthetic

interest. Finally, a DFT study has been carried out to investigate

and rationalize the formation of the different cycloadducts. The

evaluation of a variety of conceivable routes has allowed us to

propose reasonable mechanistic pictures, which in general

suggest a rate-limiting heterocyclization step.

Allyl N-(Cyclohex-3-enyl)carbamate (8). Following the general

procedure for the Curtius reaction (method A), to a solution of

cyclohex-3-enecarboxylic acid (3) (309 mg, 2.45 mmol) in dry

toluene (7.8 mL, 0.32 M) under argon were added recently distilled

Et₃N (0.41 mL, 2.94 mmol, 1.2 equiv) and DPPA (0.56 mL, 2.55

mmol, 1.04 equiv). The mixture was stirred at rt for 30 min. After

4 h at reflux, the mixture was cooled at rt, and anhydrous allylic

alcohol (0.83 mL, 12.20 mmol, 5 equiv) and CuCl (22.3 mg, 0.09

(31) Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar,

S. M. J. Org. Chem. 1993, 58, 2478.

8664 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

equiv, 99.99%) were added. Then, the reaction was warmed at

100 °C, for 2 h. The mixture was cooled, mixed with an aqueous

saturated solution of NaHCO₃, and extracted with ethyl ether (4×).

The organic phase was dried with Na₂SO₄, filtered, and evaporated.

The crude was purified by column chromatography (14% hexane/

AcOEt) to yield carbamate 8 (331 mg, 74%) as a colorless oil: IR

(film) ν 3326, 3026, 2922, 1697, 1534, 1235, 1047 cm^-1; ¹H NMR

(CDCl₃, 400 MHz) δ 5.94 (ddt, J ) 17.2, 10.5 and 5.3 Hz, 1H,

H2′), 5.72-5.66 (m, 1H, H4), 5.64-5.57 (m, 1H, H3, 5.32 (dc, J

) 17.2 and 1.5 Hz, 1H, H3′_cis), 5.22 (dc, J ) 10.4 and 1.4 Hz, 1H,

H3′_trans), 4.75 (br s, 1H, NH), 4.57 (d, J ) 5.2 Hz, 2H, CH₂O),

3.91-3.81 (m, 1H, H1), 2.40 (d J ) 17.4 Hz, 1H, H2A), 2.19-

2.10 (m, 2H, H5), 1.95-1.84 (m, 2H, H2B, H6A), 1.64-1.53 (m,

1H, H6B); ¹³C NMR (CDCl₃, 75 MHz) δ 155.6 (NHCO), 133.0

(C2′), 126.8 (CHdCH, C4), 124.3 (CHdCH, C3), 117.4 (C3′), 65.2

(C1′), 46.1 (C1), 31.8 (C2), 28.3 (C6), 23.6 (C5); MS (ES) m/z [M

+ 1]⁺182.1, [M + 23]⁺204.1, [2M + 1]⁺363.3, [2M + 23]⁺

385.0. Anal. Calcd for C₁₀H₁₅NO₂: C, 66.27; H, 8.34; N, 7.73.

Found: C, 66.09; H, 8.25; N, 7.65.

(Prop-2′-yn-1′-yl) N-(Cyclohex-3-enyl)carbamate (9). Follow-

ing the general procedure for the Curtius reaction (method A), a

solution of cyclohex-3-enecarboxylic acid (3) (672 mg, 5.33 mmol)

in dry toluene (16.6 mL, 0.32 M) was treated with Et₃N (0.89 mL,

6.38 mmol, 1.2 equiv) and DPPA (1.21 mL, 5.61 mmol, 1.05 equiv)

at 80 °C for 5 h. Then, propargylic alcohol (1.55 mL, 26.63 mmol,

5 equiv) and CuCl (55.7 mg, 0.56 mmol, 0.1 equiv) were added,

and the mixture was refluxed for 4 h. Workup and flash chroma-

tography (hexane/AcOEt, 10%) afforded compound 9 (777.3 mg,

81%) as white crystals: mp 64-6 °C; IR (KBr) ν 3301, 2947, 2130,

1717, 1686, 1543, 1434, 1273, 1237, 1052 cm^-1; ¹H NMR (CDCl₃,

300 MHz) δ 5.74-5.52 (m, 2H, H3, H4), 4.85 (br s, 1H, NH),

4.68 (d, J ) 2.4 Hz, 2H, CH₂O), 3.94-3.76 (m, 1H, H1, CHNH),

2.47 (t, J ) 2.4 Hz, 1H, CtCH), 2.40 (d, J) 17.1 Hz, 1H, H2),

2.26-2.02 (m, 2H, H5), 1.98-1.78 (m, 2H, H2′, H6), 1.70-1.50

(m, 1H, H6′); ¹³C NMR (CDCl₃, 75 MHz) δ 154.8 (NHCO₂CH₂),

126.9, 124.2 (C3, C4), 78.4 (CtCH), 74.5 (CtCH), 52.2

(NHCO₂CH₂), 46.3 (CHN, C1), 31.7 (C2), 28.2 (C6), 23.5 (C5);

MS (ES) m/z [M + 1]⁺180.1, [M + 23]⁺202.1. Anal. Calcd for

C₁₀H₁₃NO₂: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.98; H, 7.24;

N, 8.06.

C1), 35.2 (br, C2), 28.4 (C5), 27.6 (C6); MS (ES) m/z [M + 23]⁺

412.0/414.0/416.0. Anal. Calcd for C₁₄H₁₇Br₂NO₂: C, 42.99; H,

4.38; N, 3.58. Found: C, 42.79; H, 4.40; N, 3.71.

(6′-Chloro-3′-pyridyl)methyl N-(c-3,t-4-Dibromocyclohex-1-

yl)carbamate (14) and (6′-Chloro-3′-pyridyl)methyl N-(t-3,c-4-

Dibromocyclohex-1-yl)carbamate (15). Following the general

procedure for the bromination, to a solution of compound 6 (1.12

g, 4.23 mmol) in dry CH₂Cl₂(50 mL) was added Et₄NBr (9.05 g,

43.06 mol, 10.2 equiv). After being stirred for some minutes at rt,

the reaction vessel was placed in a dry ice-acetone bath at

-78 °C. Then, bromine (0.44 mL, 8.59 mol, 2.03 equiv) was added.

The reaction was pursued for 3 h stirring at -78 °C. Workup and

flash chromatography (hexane/AcOEt, 30% to AcOEt) gave

products 14 (1.06 g, 59%) and 15 (537 mg, 30%), both isolated as

white crystalline solids. 14: mp 107-9 °C; IR (KBr) ν 3358, 3045,

2939, 1693, 1531, 1463, 1276, 1107, 1046 cm^-1; ¹H NMR (CDCl₃,

300 MHz) δ 8.39 (d, J ) 2.4 Hz, 1H, H2′), 7.67 (dd, J ) 2.4 and

8.1 Hz, 1H, H4′), 7.34 (d, J ) 8.1 Hz, 1H, H5′), 5.09 (s, 2H, CH₂O),

5.05-4.95 (br s, 1H, NH), 4.24-4.0 (m, 2H, H3, H4, CHBr), 3.8-

3.6 (m, 1H, CHNH), 2.78 (d, J ) 13.5 Hz, 1H, H2A), 2.5-2.4 (m,

1H, H5A), 2.1-1.8 (m, 3H, H2B, H5B, H6A), 1.7-1.5 (m, 1H,

H6B); ¹³C NMR (CDCl₃, 75 MHz) δ 154.8 (NHCO₂CH₂Ar), 151.0

(C3′), 149.2 (C2′), 138.8 (C4′), 130.9 (C6′), 124.1 (C5′), 63.1

(NHCO₂CH₂Ar), 54.7 (C3, CHBr),* 52.9 (C4, CHBr),* 48.3 (C1,

CHNH), 42.1 (br, C2), 33.7 (br, C5), 31.5 (C6); MS (ES) m/z [M

+ 1]⁺426.9. Anal. Calcd for C₁₃H₁₅Br₂ClN₂O₂: C, 36.61; H, 3.54;

N, 6.57. Found: C, 37.17; H, 3.69; N, 6.23. 15: mp 92-95 °C; IR

(KBr) ν 3312, 3040, 2949, 1703, 1534, 1461, 1235, 1104, 1045

1

cm^-1; H NMR (CDCl₃, 300 MHz) δ 8.40 (d, J ) 1.8 Hz, 1H,

H2′), 7.68 (dd, J ) 8.0, 1.9 Hz, 1H, H4′), 7.34 (d, J ) 8.1 Hz, 1H,

H5′), 5.09 (s, 2H, CH₂O), 4.80-4.67 (br s, 1H, NH), 4.68-4.56

(m, 2H, H3, H4, CH-Br × 2), 4.17-3.95 (m, 1H, H1, CH-NH),

2.65-2.49 (m, 1H, H5A), 2.0-2.18 (m, 2H, 2 × H2) , 2.08-1.97

(m, 1H, H5B), 1.97-1.85 (m, 1H, H6A), 1.76 (qd, J ) 12.4, 3.6

Hz, 1H, H6B); ¹³C NMR (CDCl₃, 75 MHz) δ 154.9 (NHCO₂CH₂-

Ar), 151.2 (C3′), 149.4 (CH, C2′), 138.8 (CH, C4′), 131.0 (C6′),

124.1 (CH, C5′), 63.1 (NHCO₂CH₂Ar), 51.8 (CHBr, C3),* 51.3

(CHBr, C4),* 45.5 (CH-N, C1), 34.8 (CH₂, C2), 28.1 (CH₂, C5),

27.3 (CH₂, C6); MS (ES) m/z [M + 1]⁺426.9. Anal. Calcd for

C₁₃H₁₅Br₂ClN₂O₂: C, 36.61; H, 3.54; N, 6.57. Found: C, 36.35;

H, 3.69; N, 6.34.

Benzyl N-(c-3,t-4-Dibromocyclohex-1-yl)carbamate (12) and

Benzyl N-(t-3,c-4-Dibromocyclohex-1-yl)carbamate (13). Fol-

lowing the general procedure for the bromination, a solution of

benzyl N-(cyclohex-3-enyl)carbamate (5)¹¹(1.30 g, 5.62 mmol) in

dry DCM (65 mL 0.086 M) was reacted with Et₄NBr (11.97 g, 10

equiv) and Br₂(0.58 mL, 11.32 mmol, 2 equiv) at -78 °C for 2 h.

Workup and column chromatography (hexane/Et₂O, 10% to hexane/

Et₂O, 30%) gave compounds 12 (1.35 g, 61%) and 13 (546 mg,

25%). 12: mp 78-81 °C; IR (KBr) ν 3278, 3065, 2931, 1720,

1688, 1549, 1452, 1278, 1249, 1055 cm^-1; ¹H NMR (CDCl₃, 300

MHz) δ 7.36 (s, 5H, C₆H₅), 5.10 (s, 2H, CH₂O), 4.94 (br s, 1H,

NH), 4.2-4.0 (m, 2H, 2 × CHBr, H3, H4), 3.8-3.6 (m, 1H, H1,

CHNH), 2.78 (br d, J ) 13.5 Hz, 1H, H2), 2.5-2.4 (m, 1H, H5),

2.12-2.00 (m, 1H, H6), 2.0-1.8 (m, 2H, H5′, H2′), 1.5-1.3 (m,

1H, H6′); ¹³C NMR (CDCl₃, 75 MHz) δ 155.5 (NHCO₂CH₂Ph),

136.4 (C₆H_5,Cipso), 128.7 (2 × CH, C₆H₅), 128.4 (2 × CH, C₆H₅),

128.2 (CH, C₆H₅), 67.0 (NHCO₂CH₂Ph), 55.1 (CHBr, C4),* 53.1

(CHBr, C3),* 48.5 (C1, CHN), 42.4 (br, C2), 33.9, 31.7 (br; C5,

C6); MS (ES) m/z [M + 1]⁺390.0/392.1/394.0, [M + 23]⁺412.0/

414.0/415.9. Anal. Calcd for C₁₄H₁₇Br₂NO₂: C, 42.99; H, 4.38;

N, 3.58. Found: C, 42.61; H, 4.40; N, 3.72. 13: oil; IR (film) ν

Methyl N-(3-c,4-t-Dibromocyclohex-1-yl)carbamate (16) and

Methyl N-(3-t,4-c-Dibromocyclohex-1-yl)carbamate (17). Fol-

lowing the general procedure for the bromination, a solution of

compound 7 (362 mg, 2.34 mmol) in dry CH₂Cl₂(27 mL, 0.09 M)

was treated with Et₄NBr (4.92 g, 23.36 mmol, 10 equiv) and Br₂

(0.24 mL, 4.67 mmol, 2 equiv) for 3 h at -78 °C. Workup and

flash chromatography (hexane/AcOEt, 15%) gave compound 16

(382 mg, 52%) and its isomer 17 (221 mg, 30%). 16: white solid;

mp 97-9 °C; IR (KBr) ν 3301, 2947, 1719, 1692, 1548, 1447,

1278, 1048 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 4.83 (br s, NH),

4.16 (td, J ) 9.4, 3.9 Hz, 1H, H3), 4.09 (td, J ) 9.5, 3.9 Hz, 1H,

H4), 3.78-3.60 (m, 1H, H1), 3.67 (s, 3H, OCH₃), 2.78 (dm, 1H,

J ) 13.5 Hz, 1H, H2_eq), 2.56-2.45 (m, 1H, H5_eq), 2.12-2.00 (m,

1H, H6_eq), 2.00-1.90 (m, 1H, H5_ax), 1.90-1.78 (m, 1H, H2_ax),

1.49-1.30 (m, 1H, H6_ax); ¹³C NMR (CDCl₃, 100 MHz) δ 156.1

(NHCO₂CH₃), 55.2 (CHBr, C3), 53.3 (CHBr, C4), 52.2 (OCH₃),

48.4 (CHN, C1), 42.5 (br, C2), 34.1 (br, C5), 31.8 (C6); MS (ES)

m/z [M + 1]⁺315.9, [M + 23]⁺337.9. Anal. Calcd for C₈H₁₃Br₂-

NO₂: C, 30.50; H, 4.16; N, 4.45. Found: C, 30.42; H, 3.95; N,

4.50. 17: white solid; mp 104-6 °C; IR (KBr) ν 3340, 2951, 1694,

1542, 1434, 1320, 1059 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 4.94

(br s, NH), 4.64-4.59 (m, 1H, H3), 4.58-4.53 (m, 1H, H4), 4.12-

3.92 (m, 1H, H1), 3.64 (s, 3H, OCH₃), 2.55 (ddt, J ) 15.2, 12.1,

3.4 Hz, 1H, H5_ax), 2.38-2.24 (m, 1H, H2_ax), 2.18 (d, J ) 14.4 Hz,

1H, H2_eq), 2.04-1.94 (m, 1H, H H5_eq), 1.88 (br d, J ) 11.6 Hz,

1H, H6_eq), 1.73 (dtd, J ) 12.4, 12.3, 3.3 Hz, 1H, H6_ax); ¹³C NMR

(CDCl₃, 100 MHz) δ 156.3 (NHCO₂CH₃), 52.3 (OCH₃), 52.2

(CHBr, C4), 51.7 (CHBr, C3), 45.4 (CHN, C1), 35.2 (C2), 28.3

3322, 3033, 2950, 1695 (v br), 1533, 1454, 1279, 1234, 1043 cm^-1

;

¹H NMR (CDCl₃, 300 MHz) δ 7.37 (s, 5H, Ar), 5.11 (s, 2H, CH₂O),

4.69 (br s, 1H, NH), 4.64 (m, 1H, CHBr, H3),* 4.60 (m, 1H, CHBr,

H4),* 4.17-4.00 (m, 1H, H1, CHNH), 2.65-2.50 (m, 1H, H5),

2.39-2.19 (m, 2H, H2), 2.07-1.87 (m, 2H, H5′, H6), 1.84-1.67

(m, 1H, H6′); ¹³C NMR (CDCl₃, 75 MHz) δ 155.6 (NHCO₂CH₂-

Ph), 136.6 (Cipso), 128.6 (2xCH, C₆H₅), 128.2 (3xCH, C₆H₅), 66.8

(NHCO₂CH₂Ph), 52.2 (CHBr, C4),* 51.7 (CHBr, C3),* 45.6 (CHN,

J. Org. Chem, Vol. 72, No. 23, 2007 8665

Go´mez-Sa´nchez et al.

(C5), 27.6 (C6); MS (ES) m/z [M + 1]⁺315.9, [M + 23]⁺337.9.

Anal. Calcd for C₈H₁₃Br₂NO₂: C, 30.50; H, 4.16; N, 4.45. Found:

C, 30.21; H, 4.07; N, 4.32.

(NHCO₂CH₂), 78.3 (CtCH), 74.8 (CtCH), 52.5, 52.2 (2 C, C3,

C4), 51.6 (NHCO₂CH₂), 45.6 (CHN, C1), 35.0 (C2), 28.3 (C5),

27.4 (C6); MS (ES) m/z [M + 1]⁺337.9/339.9/341.9, [M + 23]⁺

359.9/361.9/363.9. Anal. Calcd for C₁₀H₁₃Br₂NO₂: C, 35.43; H,

3.86; N, 4.13. Found: C, 35.60; H, 3.83; N, 4.08.

Allyl N-(3-c,4-t-Dibromocyclohex-1-yl)carbamate (18) and

Allyl N-(3-t,4-c-Dibromocyclohex-1-yl)carbamate (19). Following

the general procedure for the bromination, to a solution of

compound 8 (114 mg, 0.63 mmol) in dry CH₂Cl₂(7.5 mL, 0.08

M) was added Et₄NBr (1.33 g, 6.31 mmol, 10 equiv), and the

resulting solution was stirred under argon at rt. After 30 min, the

solution was cooled at -78 °C, and then Br₂(0.04 mL, 0.69 mmol,

1.1 equiv) was added. After 70 min, the temperature was allowed

to rise, and workup was performed as usual. Flash chromatography

(hexane/AcOEt, 10%) gave 3-cis,4-trans-dibromide 18 (130 mg,

61%) and 3-trans,4-cis-dibromide 19 (71 mg, 33%). 18: oil; IR

(film) ν 3323, 3080, 2948, 1701, 1530, 1274, 1047 cm^-1; ¹H NMR

(CDCl₃, 500 MHz) δ 5.98-5.86 (m, 1H, H2′), 5.31 (dq, J ) 17.2

and 1.5 Hz, 1H, H3′_cis), 5.23 (dm, J ) 10.4 Hz, 1H, H3′_trans), 4.87

(br s, 1H, NH), 4.56 (d, J ) 5.5 Hz, 2H, CH₂O), 4.21-4.05 (m,

2H, H3, H4), 3.77-3.66 (m, 1H, H1), 2.79 (dm, J ) 13.5 Hz, 1H,

H2A), 2.55-2.48 (m, 1H, H5A), 2.11-2.04 (m, 2H, H6A), 2.00-

1.82 (m, 2H, H5B, H2B), 1.46-1.34 (m, 1H,H6B); ¹³C NMR

(CDCl₃, 125 MHz) δ 155.3 (NHCO₂), 132.8 (C2′), 118.2 (C3′),

65.9 (C1′), 55.0, 53.1 (C3, C4), 48.4 (C1), 42.2 (C2), 33.7 (C5),

31.7 (C6); MS (ES) m/z [M + 1]⁺339.9/341.9/343.9, [M + 23]⁺

361.9/363.9/365.9. Anal. Calcd for C₁₀H₁₅Br₂NO₂: C, 35.22; H,

4.43; N, 4.11. Found: C, 34.94; H, 4.31; N, 4.02. 19: oil; IR (KBr)

ν 3322, 3080, 2950, 1700, 1533, 1278, 1235, 1044 cm^-1; ¹H NMR

(CDCl₃, 400 MHz) δ 6.00-5.85 (m, 1H, H2′), 5.32 (d, J ) 17.1

Hz, 1H, H3′_cis), 5.22 (d, J ) 10.4 Hz, 1H, H3′_trans), 4.68 (br s, 1H,

NH), 4.64 (s with multiplicity, 1H, H3*), 4.62-4.54 (m, 3H, CH₂O

+ H4*), 4.14-4.00 (m, 1H, H1), 2.58 (ddt, J ) 15.5, 12.3, and

3.4 Hz, 1H, H5A), 2.38-2.29 (m, 1H, H2A), 2.24 (dm, J ) 14.4

Hz, 1H, H2B), 2.02 (dm, J ) 15.4 Hz, 1H, H5B), 1.98-1.88 (m,

1H, H6A), 1.76 (dc, J ) 12.4 and 3.5 Hz, 1H, H6B); ¹³C NMR

(CDCl₃, 100 MHz) δ 155.5 (NHCO₂), 133.0 (-CHdCH₂), 118.0

(-CHdCH₂), 65.8 (CH₂-O), 52.2, 51.7 (C3, C4), 45.6 (C1), 35.3

(C2), 28.4 (C5), 27.7 (C6); MS (ES) m/z [M + 1]⁺339.9/341.9/

343.9, [M + 23]⁺361.9/363.9/365.9. Anal. Calcd for C₁₀H₁₅Br₂-

NO₂: C, 35.22; H, 4.43; N, 4.11. Found: C, 35.40; H, 4.28; N,

4.25.

Heterocyclization of tert-Butyl N-(c-3,t-4-Dibromocyclohex-

1-yl)carbamate (10). Following the general procedure for the

heterocyclization reaction, dibromide 10¹²(304 mg, 0.85 mmol)

in DMF (9 mL) was reacted with NaH (52 mg, 1.30 mmol). After

1 h at 0 °C and 1 h at rt, more NaH (69 mg, 1.72 mmol, 2.0 equiv)

was added. After 5 h, the reaction was complete. Workup and

column chromatography (hexane/Et₂O, 15%, and AcOEt) afforded

2-exo-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hep-

tane (2) [¹H NMR (CDCl₃, 300 MHz) δ 4.38, 4.31 (2 br s, 2H,

H1, H4), 3.99 (dd, J ) 7.4, 3.4 Hz, 1H, H2), 2.28 (dm, J ) 13.8

Hz, 1H, H3_exo), 2.18 (dd, J ) 13.9, 7.4 Hz, 1H, H3_endo), 1.96-

1.77 (m, 1H), 1.77-1.68 (m, 1H), 1.47 (s, 9H, t-Bu), 1.44-1.23

(m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 155.0, 79.9 (C-O), 63.9,

55.7 (br) (C1, C4), 49.7 (br, C2), 43.6 (C3), 28.3 (t-Bu, C5, C6)]¹²

(122 mg, 52%) and 3a,4,5,7a-tetrahydro-2(3H)-benzooxazolone (22)

[¹H NMR (CDCl₃, 300 MHz) δ 6.14-6.20 (m, 2H, NH, H6), 5.84-

5.80 (m, 1H, H7), 4.92-4.89 (m, 1H, H7a), 4.02-3.95 (td, J )

7.6, 4.0 Hz, 1H, H3a), 2.27-2.20 (m, 1H, H5), 2.03-1.82 (m, 2H,

H4, H5′), 1.75-1.63 (m, 1H, H4′); ¹³C NMR (CDCl₃, 75 MHz) δ

160.4, 134.3, 122.6, 72.4, 51.1, 25.6, 20.7]¹⁶(30 mg, 25%).

7-[(Benzyloxy)carbonyl]-exo-2-bromo-7-azabicyclo[2.2.1]hep-

tane (23). Following the general procedure for the heterocyclization

reaction, dibromide 12 (385 mg, 0.99 mmol) in dry DMF was

reacted with NaH (55 mg, 1.38 mmol, 1.40 equiv) and stirred for

31 h. Then, more NaH (22.8 mg, 0.57 mmol, 0.56 equiv) was added,

and after 18 h, the reaction was complete. Workup and column

chromatography (CH₂Cl₂) gave compound 23 (220 mg, 72%):

white solid; mp 50-53 °C; IR (KBr) ν 3436, 3032, 2955, 1690,

1434, 1318, 1158, 1103 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 7.41-

7.28 (m, 5H, C₆H₅), 5.16 (s, 2H, CH₂O), 4.52 (br s, 1H, CH-N,

H1),* 4.40 (br s, 1H, CHN, H4),* 4.02 (dd, J ) 7.3, 3.3 Hz, 1H,

H2), 2.33 (dm, J ) 13.8 Hz, 1H, H3_exo), 2.22 (dd, J ) 13.8, 7.3

Hz, 1H, H3_endo), 1.99-1.83 (m, 1H, H6), 1.83-1.66 (m, 1H, H5),

1.50-1.41 (m, 1H, H6′), 1.39-1.28 (m, 1H, H5′); ¹³C NMR

(CDCl₃, 75 MHz) δ 155.5 (NHCOOCH₂Ph), 136.7 (C₆H_5,Cipso),

128.6 (2 × CH, C₆H₅), 128.2 (CH, C₆H₅), 128.1 (2 × CH, C₆H₅),

67.2 (NHCOOCH₂Ph), 64.2 (C1), 56.2 (C4), 49.7 (br, C2), 43.5

(br, C3), 28.3 (br, 2C, C5, C6); MS (ES) m/z [M + 1]⁺309.9/

311.9, [M + 23]⁺331.9/333.9. Anal. Calcd for C₁₄H₁₆BrNO₂: C,

54.21; H, 5.20; N, 4.52. Found: C, 54.05; H, 5.08; N, 4.64.

exo-2-Bromo-7-[(6′-chloropyridin-3′-yl)methyloxycarbonyl]-

7-azabicyclo[2.2.1]heptane (24). Following the general procedure

for the heterocyclization reaction, to a solution of carbamate 14

(263 mg, 0.617 mmol) in dry DMF (13 mL, 0.049 M) cooled at

0 °C was added NaH (51.9 mg, 1.30 mmol, 2.1 equiv, 60%

dispersion in oil) in portions, and then the temperature of the bath

was allowed to reach rt. After 27 h, usual workup and column

chromatography (hexane/AcOEt, 25%) yielded compound 24 (133

mg, 63%) as a white solid: mp 78-80 °C; IR (KBr) ν 2953, 1709,

1461, 1315, 1097 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 8.42 (d, J

) 2.3 Hz, 1H, H2′), 7.71 (dd, J ) 8.2, 2.3 Hz, 1H, H4′), 7.33 (d,

J ) 8.2 Hz, 1H, H5′), 5.14 (s, 2H, CH₂O), 4.48 (br s, 1H, CHN,

H1),* 4.42 (br s, 1H, CHN, H4),* 4.02 (dd, J ) 7.1, 3.5 Hz, 1H,

H2), 2.35-2.15 (m, 2H, H3), 2.01-1.82 (m, 1H, H6A) 1.81-1.62

(m, 1H, H5A), 1.53-1.41 (m, 1H, H6B), 1.40-1.37 (m, 1H, H5B);

¹³C NMR (CDCl₃, 75 MHz) δ 154.6 (NHCO₂CH₂Ar), 151.2 (C3′),

149.4 (C2′), 138.9 (C4′), 131.2 (C6′), 124.2 (C5′), 64.1 (C1), 63.6

(NHCO₂CH₂Ar), 56.1 (C4), 49.6 (C2), 43.3 (C3), 28.3 (C6),* 28.1

(C5);* MS (ES) m/z 265.0 [M - 79], 345.0/347.0 [M + 1]⁺, 367.0/

368.9 [M + 23]⁺. Anal. Calcd for C₁₃H₁₄BrClN₂O₂: C, 45.18; H,

4.08; N, 8.11. Found: C, 45.40; H, 4.08; N, 8.34.

Prop-2′-yn-1′-yl N-(3-c,4-t-Dibromocyclohex-1-yl)carbamate

(20) and Prop-2′-yn-1′-yl N-(3-t,4-c-Dibromocyclohex-1-yl)-

carbamate (21). Following the general procedure for the bromi-

nation, a solution of compound 9 (330 mg, 1.84 mmol) in dry

CH₂Cl₂(21 mL, 0.09 M) was reacted with Et₄NBr (3.88 g, 18.5

mmol, 10 equiv) and Br₂(0.19 mL, 3.71 mmol, 2 equiv) at -78

°C for 2.5 h. Workup and flash chromatography (hexane/AcOEt,

13%) gave 3-cis,4-trans-dibromide 20 (349 mg, 56%) and 3-trans,4-

cis-dibromide 21 (201 mg, 32%). 20 (white solid): mp 81-2 °C;

IR (KBr) ν 3413, 3240, 2957, 2134, 1716, 1519, 1452, 1276, 1220,

1

1053 cm^-1; H NMR (CDCl₃, 500 MHz) δ 5.08 (br s, 1H, NH),

4.66 (d, J ) 1.8 Hz, 2H, CH₂O), 4.20-4.12 (m, 1H, H3), 4.12-

4.04 (m, 1H, H4), 3.76-3.65 (m, 1H, H1), 2.80-2.73 (dm, J )

13.6 Hz, 1H, H2_eq), 2.53-2.46 (m, 2H, HCtC, H5_eq), 2.09-2.02

(m, 1H, H6_eq), 1.99-1.83 (m, 2H, H5_ax, H2_ax), 1.46-1.35 (m, 1H,

H6_ax); ¹³C NMR (CDCl₃, 125 MHz) δ 154.6 (NHCO₂CH₂), 78.2

(CtCH), 75.0 (CtCH), 54.9 (CHBr, C4), 53.0 (CHBr, C3), 52.7

(NHCO₂CH₂), 48.5 (CHN, C1), 41.9 (br, C2), 33.5 (br, C5), 31.5

(C6); MS (ES) m/z [M + 1]⁺337.9/339.9/341.9, [M + 23]⁺359.9/

361.9/363.9. Anal. Calcd for C₁₀H₁₃Br₂NO₂: C, 35.43; H, 3.86;

N, 4.13. Found: C, 35.40; H, 3.69; N, 4.13. 21: oil; IR (film) ν

3402, 3298, 2949, 2125, 1702, 1537, 1435, 1279, 1236, 1050 cm^-1

;

¹H NMR (CDCl₃, 400 MHz) δ 4.82 (br d, J ) 6.4 Hz, 1H, NH),

4.65 (d, J ) 2.1 Hz, 2H, CH₂O), 4.63-4.59 (m, 1H, H3), 4.58-

4.53 (m, 1H, H4), 4.09-3.96 (m, 1H, H1), 2.58-2.48 (m, 1H,

H5_eq), 2.47 (t, J ) 2.4 Hz, 1H, HCtC), 2.32 (ddd, J ) 14.3, 11.1,

3.2 Hz, 1H, H2_ax), 2.19 (dm, J ) 14.4 Hz, 1H, H2_eq), 1.98 (dm, J

) 13.8 Hz, 1H, H5_ax), 1.93-1.84 (m, 1H, H6_eq), 1.74 (dtd, J )

12.4, 12.2, 3.7 Hz, 1H, H6_ax); ¹³C NMR (CDCl₃, 100 MHz) δ 154.6

exo-2-Bromo-7-[(methoxy)carbonyl]-7-azabicyclo[2.2.1]hep-

tane (25). Following the general procedure for the heterocyclization

reaction, a solution of compound 16 (341 mg, 1.08 mmol) in dry

8666 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

DMF (22 mL, 0.05 M) was reacted with NaH (55 mg, 1.37 mmol,

1.26 equiv) for 25 h at rt. Workup and column chromatography

(hexane/AcOEt, 15%) afforded recovered starting material 16 (10

mg) and 25 [197 mg, 78% (80%, taking into account the unreacted

starting material)]: oil; IR (film) ν 2953, 1707, 1447, 1369, 1319,

1235, 1190, 1158, 1101 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 4.46

(d, J ) 4.0 Hz, 1H, H1), 4.40 (t, J ) 4.5 Hz, 1H, H4), 4.01 (dd,

J ) 7.4, 4.5 Hz, 1H, H2), 3.72 (s, 3H, OCH₃), 2.31 (dm, J ) 14.0

Hz, 1H, H3_exo), 2.21 (dd, J ) 14.0, 7.4 Hz, 1H, H3_endo), 1.90 (tdd,

J ) 12.1, 5.2, 3.7 Hz, 1H, H6_exo), 1.83-1.68 (m, 1H, H5_exo), 1.51-

1.40 (m, 1H, H6_endo), 1.39-1.28 (m, 1H, H5_endo); ¹³C NMR (CDCl₃,

100 MHz) δ 156.2 (NHCO₂CH₃), 64.2 (CHN, C1), 56.2 (CHN,

C4), 52.7 (OCH₃), 49.4 (CHBr, C2), 43.7 (C3), 28.4 (2 C, C5, C6);

MS (ES) m/z [M + 1]⁺234.1, [M + 23]⁺256.0, [2M + 23]⁺491.0.

Anal. Calcd for C₈H₁₂BrNO₂: C, 41.05; H, 5.17; N, 5.98. Found:

C, 40.89; H, 5.12; N, 5.75.

exo-2-Bromo-7-(allyloxycarbonyl)-7-azabicyclo[2.2.1]hep-

tane (26). Following the general procedure for the heterocyclization

reaction, dibromide 18 (108 mg, 0.32 mmol) in DMF (6.5 mL)

was reacted with NaH (14 mg, 0.36 mmol). After 1 h at 0 °C and

20 h at rt, more NaH (7.8 mg, 0.19 mmol, 0.61 equiv) was added.

After 22 h, starting material was still visible by NMR, so more

NaH was added (7.8 mg, 0.19 mmol, 0.61 equiv), after which time

the reaction had finished within 2 h. Workup as usual and column

chromatography (hexane/AcOEt, 10%) afforded 2-exo-bromo-7-

(allyloxycarbonyl)-7-azabicyclo[2.2.1]heptane 26 (48 mg, 58%).

26: oil; IR (film) ν 3015, 2950, 1707, 1441, 1312, 1091 cm^-1; ¹H

NMR (CDCl₃, 500 MHz) δ 5.99-5.89 (m, 1H, H2′), 5.32 (dm, J

) 17.2 Hz, 1H, H3′_cis), 5.21 (dm, J ) 10.4 Hz, 1H, H3′_trans), 4.60

(dm, J ) 5.6 Hz, 2H, 2 × H1′), 4.48 (d, J ) 4.7 Hz, 1H, H1),

4.43-4.38 (m, 1H, H4), 4.01 (dd, J ) 7.4, 3.0 Hz, 1H, H2), 2.30

(dm, J ) 13.9 Hz, 1H, H3_exo), 2.21 (dd, J ) 14.0, 7.5 Hz, 1H,

H3_endo), 1.94-1.85 (m, 1H, H6_exo), 1.81-1.70 (m, 1H, H5_exo),

1.48-1.41 (m, 1H, H6_endo), 1.38-1.30 (m, 1H, H5_endo); ¹³C NMR

(CDCl₃, 125 MHz) δ 155.3 (NHCO₂), 133.0 (C2′), 117.6 (C3′),

66.0 (C1′), 64.1 (C1), 56.1 (C4), 49.4 (C2), 43.5 (C3), 28.2 (2 C,

C5, C6); MS (ES) m/z [M + 1]⁺260.0/262.0, [M + 23]⁺282.0/

284.0, [2M + 23]⁺541.0/543.0/545.0. Anal. Calcd for C₁₀H₁₄-

BrNO₂: C, 46.17; H, 5.42; N, 5.38. Found: C, 46.35; H, 5.31; N,

5.24.

(dm, J ) 13.3 Hz, 1H, H6_eq); ¹³C NMR (CDCl₃, 100 MHz) δ 155.1

(NCO₂), 124.0 (C5′), 123.4 (C4′), 54.7 (C3*), 53.6 (C4*), 52.0

(C1), 40.8 (C2), 36.4 (C5), 29.6 (C6), 9.7 (CH₃); MS (ES) m/z

255.9/257.9/259.9, [M + 1]⁺337.6/339.6/341.9, [M + 23]⁺359.9/

361.6/363.6, [2M + 23]⁺696.5/698.5/700.5/702.5/704.7. Anal.

Calcd for C₁₀H₁₃Br₂NO₂: C, 35.43; H, 3.86; N, 4.13. Found: C,

35.18; H, 3.89; N, 3.94.

7-Acetyl-exo-2-bromo-7-azabicyclo[2.2.1]heptane (30). (A)

From Compound 2. To a solution of bromide 2 (50 mg, 0.18

mmoles) in dry CH₂Cl₂(4 mL) was added TFA (0.27 mL, 3.63

mmol, 20 equiv). The mixture was allowed to react at rt during 6

h, and then the solvent was evaporated at reduced pressure, avoiding

warming over 35 °C. The residue was dissolved in a satd aq K₂-

CO₃solution and extracted with CHCl₃(3×). The organic phases

were then dried over K₂CO₃and the solvents evaporated at T <

35 °C. The resulting crude, showing spectroscopic data [¹H NMR

(CDCl₃, 300 MHz) δ 4.12 (dd, J ) 6.9, 2.7 Hz, 1H, H2), 3.78-

3.71 (m, 2H, H1, H4), 2.20 (dd, J ) 14.4, 6.9 Hz, 1H, H3-endo),

2.04 (ddt, J ) 14.4, 5.2, 2.7 Hz, 1H, H3-exo), 1.91 (br s, 1H, NH),

1.78 (tdd, J ) 12.2, 5.2, 3.2 Hz, 1H), 1.69-1.56 (m, 1H), 1.34-

1.13 (m, 2H)] identical to those described in the literature for exo-

2-bromo-7-azabicyclo[2.2.1]heptane (29),¹²was then submitted to

standard acetylation conditions [pyridine (2 mL), Ac₂O (2 mL)]

during 17 h. The reagents were then coevaporated with toluene at

reduced pressure, and the crude was purified by chromatographic

column using silica gel and AcOEt/MeOH/NH₃(6:94:0.3) as eluent,

yielding compound 30 (30 mg, 76%) of as a white solid: mp 64-

6 °C; IR (KBr) ν 2952, 1643, 1449, 1419 cm^-1; ¹H NMR (CDCl₃,

400 MHz) δ 4.79 (d, J ) 5.6 Hz, 1H, H1) (minor invertomer),

4.72 (t, J ) 4.6 Hz, 1H, H4) (major invertomer), 4.27 (d, J ) 5.2

Hz, 1H, H1) (major invertomer), 4.21 (t, J ) 4.2 Hz, 1H, H4)

(minor invertomer), 4.07 (dd, J ) 3.6, 6.8 Hz, 1H, H2) (major

invertomer), 4.03 (dd, J ) 3.8, 6.6 Hz, 1H, H2) (minor invertomer),

2.31-2.26 (m, 2H, H3) (minor invertomer), 2.23-2.17 (m, 2H,

H3) (major invertomer), 2.11 (s, 3H, COCH₃) (major invertomer),

2.07 (s, 3H, COCH₃) (minor invertomer), 1.96-1.83 (m, H6 exo,

both invertomers), 1.78-1.65 (m, 1H, H5 exo, both invertomers),

1.56-1.47 (m, 1H, H6 endo, major invertomer), 1.45-1.39 (m,

H6 endo, H5 endo, minor invertomer), 1.35-1.27 (m, 1H, H5 endo,

major invertomer); ¹³C NMR (CDCl₃, 100 MHz) δ 167.7 (NCOCH₃),

64.7 (C1, major invertomer), 61.1 (C1, minor invertomer), 56.7

(C4, minor invertomer), 53.0 (C4, major invertomer), 50.4 (C2,

major invertomer), 48.2 (C2, minor invertomer), 44.5 (C3, minor

invertomer), 42.8 (C3, major invertomer), 29.5 (C6, minor inver-

tomer), 28.9 (C6, major invertomer), 27.7 (C5, major invertomer),

27.0 (C5, minor invertomer), 21.7 (major invertomer) and 21.5

(major invertomer) (COCH₃); MS (ES) m/z [M + 1]⁺218.1/220.1,

[M + 23]⁺240.1/242.1. Anal. Calcd for C₈H₁₂BrNO: C, 44.06;

H, 5.55; N, 6.42. Found: C, 43.78; H, 5.40; N, 6.33. (B) From

Compound 41. To a solution of 2,2,2-trifluoroacetamide 41 (161

mg, 0.59 mmol) in MeOH/H₂O (7:3, 10 mL) was added K₂CO₃

(416 mg, 3.00 mmol, 5 equiv), and the mixture was stirred for 21

h at rt. The solvent was removed, and the residue was suspended

in an aqueous saturated solution of K₂CO₃, and extracted with

CHCl₃(5×). The organic phase was dried, filtered, and evaporated.

The crude was acetylated under the usual conditions [pyridine (2

mL), Ac₂O (2 mL), rt, 50 h). After solvent removal, the crude was

purified by flash chromatography (AcOEt/MeOH/NH₃, 94:6:4)

giving compound 30 (93 mg, 72%).

3-((1SR,3SR,4SR)-3,4-Dibromocyclohexyl)-4-methyleneoxazo-

lidin-2-one (27). Following the general procedure for the hetero-

cyclization reaction, a solution of dibromide 20 (30 mg, 0.09 mmol)

in dry DMF (0.9 mL, 0.1 M) was reacted with NaH (4.3 mg, 0.11

mmol, 1.2 equiv) at rt for 4.5 h, until starting material disappeared

(TLC). Workup and column chromatography (hexane/AcOEt, 15%)

yielded compound 27 (12.6 mg, 42%): oil; IR (film) ν 3150, 2953,

1740, 1662, 1377, 1235 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 4.82

(t, J ) 2.3 Hz, 2H, CH₂O), 4.24 (dt, J ) 3.3, 2.6 Hz, 1H, dCHA),

4.15 (dt, J ) 3.4, 2.1 Hz, 1H, dCHB), 4.06-4.01 (m, 2H, H3,

H4), 3.65 (tt, J ) 12.4, 3.9 Hz, 1H, H1), 2.79 (dt, J ) 13.1, 12.2

Hz, 1H, H2_ax), 2.60 (dc, J ) 13.9, 3.7 Hz, 1H, H5_ec), 2.50 (dtd, J

) 13.1, 3.9, 2.8 Hz, 1H, H2_eq), 2.35 (dtd, J ) 12.5, 13.3, 3.7 Hz,

1H, H6_ax), 2.04-1.90 (m, 1H, H5_ax), 1.82 (dm, J ) 13.2 Hz, 1H,

H6_eq); ¹³C NMR (CDCl₃, 100 MHz) δ 156.2 (NCO₂CH₂), 140.2

(CdCH₂), 81.3 (CdCH₂), 66.9 (NCO₂CH₂), 55.0, 53.9 (2 C, C3,

C4), 51.4 (C1), 39.3 (C2), 36.4 (C5), 28.1 (C6); MS (ES) m/z [M

+ 1]⁺337.9/339.9/341.9, [M + 23]⁺359.9/361.9/363.7, [2M +

23]⁺698.7/700.7/702.8. Anal. Calcd for C₁₀H₁₃Br₂NO₂: C, 35.43;

H, 3.86; N, 4.13. Found: C, 35.54; H, 3.90; N, 3.97. Compound

27 slowly isomerizes to 3-[(1SR,3SR,4SR)-3,4-dibromocyclo-

hexyl]-4-methyloxazol-2(3H)-one (28) as detected after storage

for 5 months at 5-20 °C and isolation by flash chromatography

(1% CH₂Cl₂/MeOH): oil; IR (film) ν 2926, 2342, 2360, 1738, 1444

7-[(tert-Butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31).

To a solution of bromide 2 (175 mg, 0.63 mmol) in dry THF (8

mL, 0.08 M) under argon, at rt, was added t-BuOK (84 mg, 0.71

mmol, 1.12 equiv), and the suspension was refluxed for 3.5 h. Then,

further t-BuOK (38 mg, 0.32 mmol, 0.5 equiv) was added, and the

reflux was continued for 1.5 h. The mixture was cooled at rt, brine

was added, and the mass was extracted with ethyl ether (3×). The

organic layer was dried (Na₂SO₄), filtered, and evaporated. The

crude was submitted to column chromatography (hexane/AcOEt,

5%), to give compound 31 (96 mg, 78%) [¹H NMR (CDCl₃, 300

1

cm^-1; H NMR (CDCl₃, 400 MHz) δ 6.54 (q, J ) 1.6 Hz, 1H,

H5′), 4.06-4.01 (m, 2H, H3, H4), 3.66 (tt, J ) 12.4, 4.0 Hz, 1H,

H1), 2.90-2.80 (m, 1H, H2_ax), 2.61 (dm, J ) 14.0 Hz, 1H, H5_ec),

2.55-2.49 (dm, J ) 13.1 Hz, 1H, H2_eq), 2.47-2.34 (m, 1H, H6_ax),

2.02 (d, J ) 1.6 Hz, 3H, CH₃); 2.00-1.90 (m, 1H, H5_ax), 1.84

J. Org. Chem, Vol. 72, No. 23, 2007 8667

Go´mez-Sa´nchez et al.

MHz) δ 6.22 (s, 2H, H2, H3), 4.65 (s, 2H, H1, H4), 1.84 (d, J )

9.3 Hz, 2 H), 1.42 [s, 9H, OC(CH₃)₃], 1.09 (d, J)7.8 Hz, 2 H);

¹³C NMR (CDCl₃, 75 MHz) δ 155.3 (NHCOO), 134.8 (2C, C2,

C3), 79.8 [OC(CH₃)₃], 59.7 (2C, C1, C4), 28.4 [OC(CH₃)₃], 24.0

(2C, C5, C6)] identical to those described in the literature for the

same compound.¹⁴

5.91 (dt, J ) 10.0, 3.6 Hz, 1H, H4), 5.82 (ddt, J ) 10.0, 4.4, 2.1

Hz, 1H, H3), 5.34 (br d, J ) 6.8 Hz, 1H, NH), 5.12 (s, 2H, CH₂O),

4.14 (br s, 1H, CHOH, H2), 3.85-3.75 (m, 1H, CHN, H1), 2.21-

2.12 (m, 2H, H5), 2.10-1.98 (br s, OH), 1.85-1.76 (m, 1H, H6),

1.72-1.58 (m, 1H, H6′); ¹³C NMR (CDCl₃, 100 MHz) δ 156.2

(NCO₂CH₂C₆H₅), 136.7 (Cipso, C₆H₅), 132.0 (C4), 128.7 (3xCH,

C₆H₅), 128.3 (2xCH, C₆H₅), 127.3 (C3), 66.9 (NCO₂CH₂C₆H₅), 65.3

(CHOH, C2), 50.8 (CHN, C1), 24.9 (CH₂, C5), 23.6 (CH₂, C6)]

previously described in the literature.^16c

7-Carbomethoxy-7-azabicyclo[2.2.1]hept-2-ene (32). To a

solution of bromide 25 (100 mg, 0.43 mmol) of in dry THF (7

mL, 0.06 M) was added t-BuOK (68 mg, 0.60 mmol, 1.40 equiv)

in small portions. The resulting solution was then heated under

reflux during 4 h, after which 25 mg more of t-BuOK (0.22 mmol,

0.5 equiv) was added. After 1 h, the starting material was no longer

detectable by TLC analysis, and the mixture was allowed to reach

rt and then added to 5 mL of a satd aq solution of NaCl. The

aqueous solution was extracted with ether (3×), and the organic

phases were dried over Na₂SO₄and evaporated to afford 32 (80%),

which showed spectroscopic data [¹H NMR (CDCl₃, 300 MHz) δ

6.23 (s, 2H, H2, H3), 4.72 (s, 2H, H1, H4), 3.63 (s, 3H, OCH₃),

1.91-1.80 and 1.18-1.04 (m, 4, 2H5, 2H6) ¹³C NMR (CDCl₃, 75

MHz): δ 156.1 (NHCO₂CH₃), 134.9 (br s, 2 C, C2, C3), 59.7 (2

C, C1, C4), 52.6 (NHCO₂CH₃), 24.0 (2 C, C5, C6)] similar to the

same product previously described in the literature.^18b

6-Aminocyclohex-2-enol (33). To a solution of 3a,4,5,7a-

tetrahydro-2(3H)-benzooxazolone (22) (70 mg, 0.5 mmol) in 1,4-

dioxane (12.5 mL, 0.04 M) was added an aqueous solution of LiOH

2N (1.25 mL, 2.5 mmol, 5 equiv). The mixture was stirred ar rt for

68 h, 29 h at 60 °C, and 7 days at reflux. The crude was cooled,

the solvent removed, and the residue suspended in brine and

extracted with AcOEt. The organic layer was dried (Na₂SO₄) and

filtered, and the solvents were evaporated. The resulting crude was

purified by column chromatography (CH₂Cl₂/MeOH, 1% to CH₂-

Cl₂/MeOH/NH_3,85: 15: 4) to give starting material 22 (18 mg,

26%) and compound 33 [(26 mg, 46% (63% taking into account

the recovered starting material)]: red solid; mp 66-70 °C; IR (KBr)

ν 3435, 3026, 2920, 1631, 1462, 1382, 1068, 1000 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 5.88-5.72 (m, 2H, H2, H3), 4.02 (br s with

multiplicity, 1H, H1), 2.97 (dt, J ) 9.3, 3.9 Hz, 1H, H6), 2.28 (br

s, 3H, NH₂, OH), 2.24-1.96 (m, 2H, 2xH4), 1.75-1.55 (m, 2H,

2xH5); ¹³C NMR (CDCl₃, 100 MHz) δ 130.4, 128.4 (C2, C3), 66.0

(C1), 50.1 (C6), 26.6 (C5), 24.0 (C4); MS (ES) m/z [M + 1]⁺114.1.

Anal. Calcd for C₆H₁₁NO: C, 63.68; H, 9.80; N, 12.38. Found:

C, 63.51; H, 9.70; N, 12.24.

6-Acetamidocyclohex-2-enyl Acetate (34). Amino alcohol 33

(19 mg, 0.17 mmol) was treated with Ac₂O (2 mL) and pyridine

(2 mL) for 83 h at rt. The solvents were removed in vacuo and the

residue purified by column chromatography (CH₂Cl₂/MeOH, 1%),

affording compound 34 (24.7 mg, 74%): mp 86-8 °C; IR (KBr)

ν 3440, 3319, 3031, 2908, 1729, 1643, 1541, 1237 cm^-1; ¹H NMR

(CDCl₃, 500 MHz) δ 5.96 (dt, J ) 10.0, 3.4 Hz, 1H, H3), 5.81

(ddt, J ) 9.8, 4.4, 2.2 Hz, 1H, H2), 5.70 (br d, J ) 7.1 Hz, 1H,

NH), 5.19-5.15 (m, 1H, H1), 4.28-4.19 (m, 1H, H6), 2.23-2.17

(m, 2H, 2 × H4), 2.08 (s, 3H, OCOCH₃), 1.99 (s, 3H, NHCOCH₃),

1.80-1.74 (m, 2H, 2 × H5); ¹³C NMR (CDCl₃, 125 MHz) δ 170.5

(OCOCH₃), 169.6 (NHCOCH₃), 133.3 (C3), 124.0 (C2), 68.3 (C1),

46.8 (C6), 24.6 (C4), 24.0 (C5), 23.7 (NHCOCH₃), 21.4 (OCOCH₃);

MS (ES) m/z [M - 59]⁺138.1, [M + 1]⁺198.1, [M + 23]⁺220.1,

[2M + 1]⁺395.2, [2M + 23]⁺417.1. Anal. Calcd for C₁₀H₁₅NO₃:

C, 60.90; H, 7.67; N, 7.10. Found: C, 60.75; H, 7.65; N, 7.09.

Benzyl (1SR,2RS)-2-Hydroxycyclohex-3-enylcarbamate (35).

To a solution of amino alcohol 33 (5.9 mg, 0.05 mmol) in anhyd

CH₂Cl₂(0.1 mL) was added dimethylaminopyridine (26.4 mg, 0.21

mmol, 4.1 equiv) and then benzyloxycarbonyl chloride (8.2 µL,

0.06 mmol, 1.05 equiv) at 0 °C. After 20 h, distilled water was

added, and the aqueous phase was extracted with CH₂Cl₂. The

organic phases were dried over Na₂SO₄, and the residue, after

distillation at reduced pressure, was purified by silica gel column

chromatography (1.2% CH₂Cl₂/MeOH), which yielded product 35

(1.4 mg, 11%) showing good correlation with the spectroscopic

data [¹H NMR (CDCl₃, 400 MHz) δ 7.41-7.29 (m, 5H, C₆H₅),

Heterocyclization of tert-Butyl N-(t-3,c-4-Dibromocyclohex-

1-yl)carbamate (11). Following the general procedure for the

heterocyclization reaction, dibromide 11¹²(219.7 mg, 0.62 mmol)

in dry DMF (6.4 mL) was reacted with NaH (37.1 mg, 0.928 mmol).

Three hours after the first addition, a further portion of NaH was

added (50.8 mg, 1.27 mmol). After 4 h, workup, column chroma-

tography (hexane/Et₂O, 10% to hexane/Et₂O, 60%) gave compound

22 (37.4 mg, 44%) and a mixture of compounds 36 + 37 {33.8

mg, in a 3.6: 1 ratio, as determined by GC/MS analysis [column

(methylsilicon as stationary phase, 0.2 mm internal diameter, 25

m long, and 0.33 µ width), He as transporter gas, 70-270 °C at

4 °C/min]}: 36 34.65 min (MS m/z 219, 221 (3, 3), 98 (100), 68

(8), 41 (17); 37 24.60 min (MS m/z 139 (M⁺, 19), 94 (100), 80

(46), 67 (60), 39 (33). After careful chromatography, we could

isolate only small amounts of the pure components. 36: white solid;

mp 133-5 °C; IR (KBr) ν 3262, 2953, 1698, 1445, 1268, 1115,

1

cm^-1; H NMR (CDCl₃, 400 MHz) δ 6.28 (br s, 1H, NH, H4),

4.74-4.71 (m, W_h/2) 8.0 Hz, 1H, H1), 4.11 (ddd, J ) 10.0, 8.3,

2.0 Hz, 1H, H8), 3.74-3.71 (m, W_h/2) 10.0 Hz, 1H, H5), 2.31-

2.22 (m, 3 H, 2H7, H9), 1.96-1.88 (m, 2H, H9′, H6), 1.60-1.74

(m, 1H, H6′); ¹³C NMR (CDCl₃, 100 MHz) δ 154.2 (NHCOO,

C3), 76.7 (CHO, C1), 50.5 (CHBr, C8), 44.5 (CHN, C5), 33.2 (C6),

30.3 (C9), 27.9 (C7); MS (ES) m/z [M + 1]⁺219.9/221.9, [M +

23]⁺241.9/243.9, [2M + 1]⁺439.0/441.0/442.9, [2M + 23]⁺460.9/

462.9/465.0. Anal. Calcd for C₇H₁₀BrNO₂: C, 38.20; H, 4.58; N,

6.36. Found: C, 38.09; H, 4.32; N, 6.09. 37: white solid; mp 185-

1

7 °C; H NMR (CDCl₃, 400 MHz) δ 6.12-6.04 (m, 1H, H8),*

6.00-5.92 (m, 1H, H7),* 5.33 (br s, 1H, NH), 4.75-4.73 (m, W_h/2

) 12.1 Hz, 1H, H1), 3.89-3.83 (m, W_h/2) 11.0 Hz, 1H, H5),

2.39-2.31 (m, 2H, 2H6), 2.29-2.18 (m, 1H, H9), 1.92 (dm, J )

13.2 Hz, 1H, H9′); ¹³C NMR (CDCl₃, 100 MHz) δ (CdO signal

hidden by noise), 129.6, 125.8 (C7, C8), 68.0 (CHO, C1), 44.8

(CHN, C5), 35.0 (C6), 26.9 (C9); MS (ES) m/z [M + 1]⁺140.1,

[M + 23]⁺162.1, [2M + 1]⁺279.0, [M + 23]⁺301.0; HRMS

calcd for C₇H₉NO₂162.0525 (M + Na⁺), found 162.0530 (M +

Na⁺).

Heterocyclization of Benzyl N-(t-3,c-4-Dibromocyclohex-1-

yl)carbamate (13). Following the general procedure for the

heterocyclization reaction, dibromide 13 (203 mg, 0.52 mmol) in

dry DMF (11 mL) was reacted with NaH (31 mg, 0.77 mmol, 1.49

equiv), at rt for 72 h; then, more NaH (31 mg, 0.78 mmol, 1.5

equiv) was added. After 24 h at rt, workup and column chroma-

tography (hexane/AcOEt, 20%; CH₂Cl₂/MeOH, 1-5%) provided

compounds 38 (27 mg, 17%) and 35 (15 mg, 12%).^16c3-(Benzyl-

oxy)-8-bromo-2-oxa-4-azabicyclo[3.3.1]non-3-ene (38): white

solid; mp 122-4 °C; IR (KBr) ν 3026, 2938, 1685, 1448, 1233,

1

1123 cm^-1; H NMR (CDCl₃, 300 MHz) δ 7.50-7.46 (m, 5H,

C₆H₅), 5.15 (s, 2H, OCH₂C₆H₅), 4.74-4.68 (m, 1H, CHO, H1),

4.13 (ddd, J ) 11.8, 5.6, 1.8 Hz, 1H, CHBr, H8), 3.77 (br s, 1H,

CHN, H5), 2.24-1.88 (m, 4H, 2H7, H6, H9), 1.82 (br d, J ) 13.5

Hz, 1H, H9ax), 1.76-1.50 (m, 1H, H6); ¹³C NMR (CDCl₃, 75

MHz) δ 154.1 [NdC(O CH₂C₆H₅)O], 136.4 (C ipso), 128.6 (2 ×

CH, C₆H₅), 128.1 (CH, C₆H₅), 128.0 (2xCH, C₆H₅), 76.5 (CHO,

C1), 69.2 (OCH₂C₆H₅), 52.3 (CHBr, C8), 45.3 (CHN, C5), 32.6

(CH₂, C6), 30.0 (CH₂, C9), 28.3 (CH₂, C7); MS (ES) m/z [M +

1]⁺309.9/311.9, [M + 23]⁺331.9/333.9. Anal. Calcd for C₁₄H₁₆-

BrNO₂: C, 54.21; H, 5.20; N, 4.52. Found: C, 53.98; H, 5.05; N,

4.73.

6-(Benzyloxycarbonylamino)cyclohex-2-enyl acetate (39). Ben-

zyl 2-hydroxycyclohex-3-enylcarbamate (35) (11.6 mg, 0.046

8668 J. Org. Chem., Vol. 72, No. 23, 2007

Synthesis of 7-Azabicyclo[2.2.1]heptane DeriVatiVes

mmol) was treated with Ac₂O (2 mL) and pyridine (2 mL) at rt for

85 h. Evaporation of solvents and column chromatography of the

residue (hexane/AcOEt, 25%) furnished acetate 39 (8.5 mg, 64%)

as a white solid: mp 64-6 °C; IR (KBr) ν 3428, 3363, 3038, 2938,

1721, 1683, 1525, 1301, 1252, 1045 cm^-1; ¹H NMR (CDCl₃, 400

MHz) δ 7.42-7.30 (m, 5H, C₆H₅), 5.96 (dt, J ) 9.9, 3.5 Hz, 1H,

H3), 5.84-5.76 (m, 1H, H2), 5.22 (t, J ) 4.0 Hz, 1H, H1), 5.11

(s, 2H, CH₂O), 4.98 (br d, J ) 8.4 Hz, 1H, NH), 4.07-3.97 (m,

1H, CHN, H6), 2.24-2.17 (m, 2H, H4), 2.05 (s, 3H, OCOCH₃),

1.86-1.74 (m, 2H, H5); ¹³C NMR (CDCl₃, 100 MHz) δ 170.3

(OCOCH₃), 155.7 (NCO₂CH₂C₆H₅), 136.3 (Cipso), 132.9 (C3),

128.5, 128.3, 128.2 (5xCH, C₆H₅), 123.9 (C2), 68.4 (CHO, C1),

66.8 (NCO₂CH₂C₆H₅), 48.4 (CHN, C6), 24.3, 24.2 (2 C, C4, C5),

21.1 (OCOCH₃); MS (ES) m/z [M + 23]⁺312.0. Anal. Calcd for

C₁₆H₁₉NO₄: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.35; H, 6.71;

N, 4.74.

exo-2-Bromo-7-(2,2,2-trifluoroacetyl)-7-azabicyclo[2.2.1]hep-

tane (41). Following the general procedure for the heterocyclization

reaction, a solution of compound 40¹²(4.61 g, 13.06 mmol) in dry

DMF (150 mL, 0.087 M), was reacted with NaH (629 mg, 15.72

mmol, 1.20 equiv). After 22 h, workup and column chromatography

(hexane/AcOEt, 20%) gave product 41 (2.86 g, 81%): mp 45-8

°C; IR (KBr) ν 2961, 1690, 1475, 1244, 1191, 1150 cm^-1; ¹H NMR

(CDCl₃, 400 MHz) δ 4.92 (d, J ) 5.6 Hz, 1H, H1), 4.86-4.83 (m,

1H, H4), 4.13-4.05 (m, 1H, H2), 2.33-2.29 (m, 2H, 2H3), 2.06-

1.93 (m, 1H, H6 exo), 1.91-1.79 (m, 1H, H5 exo), 1.69-1.43 (m,

2H, H5 endo, H6 endo); ¹³C NMR (CDCl₃, 100 MHz) δ 153.7 (q,

²J_C-F) 37.2 Hz, NCOCF₃), 116.6 (q, ¹J_C-F) 288.2 Hz, NCOCF₃),

63.0 (C1), 55.3 (C4), 48.0 (C2), 42.4 (C3), 27.3 (C5), 26.6 (C6);

MS (ES) m/z [M + 1]⁺272.0/274.0, [M + 23]⁺294.0/296.0, [2M

+ 23]⁺565.0/567.0/569.0. Anal. Calcd for C₈H₉BrF₃NO: C, 35.32;

H, 3.33; N, 5.15. Found: C, 35.39; H, 3.41; N, 5.12.

¹³C NMR (CDCl₃, 100 MHz) δ 170.1 (OCOCH₃), 169.3 (NH-

COCH₃), 71.2 (C1), 53.6 (C2), 45.9 (C5), 33.0 (C6), 30.4 (C3),

26.9 (C4), 23.6 (NHCOCH₃), 21.2 (OCOCH₃); MS (ES) m/z [M

+ 1]⁺278.0/230.0, [M + 23]⁺300.0/302.0, [2M + 1]⁺555.0/

557.0/559.0. Anal. Calcd for C₁₀H₁₆BrNO₃: C, 43.18; H, 5.80; N,

5.04. Found: C, 43.40; H, 5.99; N, 5.02.

N-(3-Oxocyclohexyl)acetamide (46).²⁰To a solution of com-

pound 45 (157 mg, 0.56 mmol) in dry THF (7.5 mL, 0.075 M),

t-BuOK (73 mg, 0.64 mmol, 1.13 equiv) was added at rt, under

argon. The mixture was refluxed for 23 h. Then, more t-BuOK (36

mg, 0.31 mmol, 0.56 equiv) was added; after 5 h, a similar aliquot

of t-BuOK (36 mg, 0.31 mmol, 0.56 equiv) was added again. After

2 h at reflux, the mixture was cooled, brine was added, and the

reaction was extracted with ethyl ether (4×). The organic phase

was dried (Na₂SO₄), filtered, and the solvent removed. The crude

was submitted to chromatography (hexane/AcOEt, 1:1 to AcOEt),

yielding compound 46 (34.3 mg, 39%): viscous oil; IR (film) ν

3292, 2941, 1709, 1655, 1549, 1223 cm^-1; ¹H NMR (CDCl₃, 300

MHz) δ 5.49 (br s, 1H, NH), 4.35-4.20 (tt, J ) 12.6, 4.0 Hz, 1H,

H1_ax), 2.71 (dd, J ) 14.0, 4.8 Hz, 1H, H2_eq), 2.47-2.20 (m, 3H,

H2_ax, 2H4), 2.14-1.91 (m, 2H, H5, H6), 2.00 (s, 3H, CH₃), 1.87-

1.58 (m, 2H, H5′, H6′); ¹³C NMR (CDCl₃, 75 MHz) δ 209.1 (C3),

169.4 (NHCOCH₃), 48.7 (C1), 47.8 (C2), 41.1 (C4), 30.9 (C6),

23.6 (CH₃), 22.3 (C5); MS (ES) m/z [M + 1]⁺156.1, [M + 23]⁺

178.1, [2M + 23]⁺333.3. Anal. Calcd for C₈H₁₃NO₂: C, 61.91;

H, 8.44; N, 9.03. Found: C, 61.75; H, 8.15; N, 8.79.

Reaction of 8-Bromo-3-(trifluoromethyl)-2-oxa-4-azabicyclo-

[3.3.1]non-3-ene (43) with Potassium tert-Butoxide. To a solution

of dihydro-1,3-oxazine 43 (106 mg, 0.39 mmol) in dry THF (5.5

mL, 0.076 M) was added t-BuOK (53 mg, 0.46 mmol, 1.18 equiv)

at rt, under argon. The resulting mixture is then heated under reflux

for 3 h, and more t-BuOK (23 mg, 0.20 mmol, 0.52 equiv) was

added. After 1 h more at reflux, the reaction was cooled, brine

was added, and extracted with ethyl ether (3×). The organic phase

was dried (Na₂SO₄), filtered, and evaporated. The crude was purified

by column chromatography (hexane/AcOEt, 15% f 30%) provid-

ing N-(4-bromocyclohex-3-enyl)-2,2,2-trifluoroacetamide (47) (70

mg, 66%): white solid; mp 120-2 °C; IR (KBr) ν 3416, 3294,

8-Bromo-3-(trifluoromethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-

ene (43). Following the general procedure for the heterocyclization

reaction, a solution of compound 42¹²(328.9 mg, 0.932 mmol) in

dry DMF (16 mL) was treated with NaH (46 mg, 1.15 mmol, 1.23

equiv). After 22 h, workup and flash chromatography (hexane/

AcOEt, 30%) provided compound 43 (201 mg, 79%): mp 130-

2 °C; IR (film) ν 2950, 1688, 1450, 1392, 1321, 1276, 1208, 1133

cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 4.83-4.76 (m, 1H, H1), 4.15

(ddd, J ) 12.2, 5.6, 2.1 Hz, 1H, H8), 4.00-3.93 (m, 1H, H5), 2.29-

2.16 (m, 1H, H7), 2.14-1.99 (m, 2H, H9, H6), 1.98-1.94 (m, 1H,

H9′), 1.94-1.86 (m, 1H, H7′), 1.86-1.70 (m, 1H, H6′); ¹³C NMR

1

3103, 2935, 1702, 1562, 1248, 1203, 1184, 1162 cm^-1; H NMR

(CDCl₃, 400 MHz) δ 6.28 (br s, 1H, NH), 6.02-5.97 (m, W_h/2

)

8.9 Hz, 1H, H3), 4.25-4.15 (m, W_h/2) 18.5 Hz, 1H, H1), 2.70-

2.58 (m, 1H, H2), 2.58-2.48 (m, 2H, H5, H6), 2.13-1.97 (m, 2H,

H2′, H5′), 1.93-1.82 (m, 1H, H6′); ¹³C NMR (CDCl₃, 100 MHz)

δ 157.0 (q, ²J_C-F) 36.9 Hz, COCF₃), 125.5 (BrCdCH, C3), 121.8

2

(CDCl₃, 75 MHz) δ 149.4 [q, J_C-F) 153.8 Hz, N)C(O)CF₃],

116.8 (q, ¹J_C-F) 1100.8 Hz, CF₃), 76.1 (CHO, C1), 51.0 (CHBr,

C8), 45.4 (CHN, C5), 31.0 (C6), 28.9 (C9), 28.0 (C7); MS (ES)

m/z [M + 1]⁺272.0/274.0. Anal. Calcd for C₈H₉BrF₃NO: C, 35.32;

H, 3.33; N, 5.15. Found: C, 35.12; H, 3.39; N, 4.98.

1

(BrCdCH, C4),116.0 (q, J_C-F) 288.1 Hz, NHCOCF₃), 44.5 (d,

⁴J_C-F)3.6 Hz, C1), 33.0, 32.9 (C2, C5), 29.1 (C6); MS (ES) m/z

[M + 1]⁺272.0/274.0, [M + 23]⁺293.9/296.0. Anal. Calcd for

C₈H₉BrF₃NO: C, 35.32; H, 3.33; N, 5.15. Found: C, 35.07; H,

3.42; N, 5.35.

5-Acetamido-2-bromocyclohexyl Acetate (45). To a solution

of compound 43 (91 mg, 0.33 mmol) in THF/H₂O [21 mL:7 mL

(3:1), 0.012 M] was added trifluoroacetic acid (0.5 mL, 6.73 mmol,

20 equiv) at rt. After 2.5 h, the solvents were evaporated, and the

crude amino alcohol 44 [¹H NMR (D₂O, 300 MHz) δ 4.42-4.37

(m, 1H), 3.53 (dt, J ) 10.9 and 3.6 Hz, 1H), 3.11 (tt, J ) 15.6,

10.4 and 4.7 Hz, 1H), 2.01 (dq, J ) 15.1 and 3.6 Hz, 1H), 1.85-

1.54 (m, 5H); ¹³C NMR (D₂O, 75 MHz) δ 162.7 (q, J ) 36.1 Hz),

116.2 (q, J ) 291.2 Hz), 68.3, 58.0, 47.6, 32.8, 29.1, 24.0] was

acetylated as usual [pyridine (2 mL), Ac₂O (2 mL), 27 h, rt]. After

evaporation of the solvents, the residue was purified by column

chromatography (DCM/MeOH, 5%) to give compound 45 (92 mg,

100%): white solid; mp 122-4 °C; IR (KBr) ν 3428, 3290, 2932,

1741, 1650, 1555, 1367, 1234, 1038 cm^-1; ¹H NMR (CDCl₃, 400

MHz) δ 5.58 (d, J ) 6.5 Hz, 1H, NH), 4.71 (dt, J ) 11.0, 3.6 Hz,

1H, H1), 4.65-4.60 (m, W_h/2) 7.9 Hz, 1H, H2), 4.02-3.91 (W_h/2

) 23.7 Hz, 1H, H5), 2.16 (dq, J ) 15.2, 3.9 Hz, 1H, H3_eq), 2.10

(s, 3H, OCOCH₃),* 2.04-1.94 (m, 2H, H3_ax, H6), 1.98 (s, 3H,

NHCOCH₃),* 1.87-1.75 (m, 2H, H6′, H4_eq), 1.68 (qd, J ) 12.1,

3.9 Hz, 1H, H4_ax) [deuterium exchange with D₂O shows that the

multiplet at 4.02-3.91 is simplified (3.97, tt, J ) 11.2, 4.4 Hz)];

Computational Methods. All of the calculations were carried

out using the Gaussian98 and Gaussian03 packages.³²In the gas

phase, all structures were fully optimized at the mPW1PW91 level.³³

Despite the most popular version of a hybrid DFT method is

B3LYP, which provides excellent low-cost performance for ge-

ometry optimizations, the hybrid mPW1PW91 functional, which

uses the modified Perdew-Wang exchange functional that has

improved the long-range behavior, has been reported to give better

results in some cases. DFT models may substantially underestimate

the activation energies for SN₂substitution reactions, a kind of

process present in this study, and where the mPW1PW91 functional

has shown good performance.³⁴

As the present study involves anions, which have a more spread-

out electron density than neutral atoms, it is essential to add diffuse

(32) (a) Frisch, M. J. et al. Gaussian98, Revision A.11; Gaussian, Inc.,

Pittsburgh, PA, 2001. (b) Frisch, M. J. et al. Gaussian03, Revision B.03;

Gaussian, Inc., Pittsburgh PA, 2003. (See the Supporting Information.)

(33) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664.

(34) Kormos, B. L.; Cramer, C. J. J. Phys. Org. Chem. 2002, 15, 712.

J. Org. Chem, Vol. 72, No. 23, 2007 8669

Go´mez-Sa´nchez et al.

functions in the basis set,³⁵and the 6-31+G(d,p) basis sets was

used, except for Br atom which was described by means of the

3-21G(d) basis set. Zero-point energies (ZPEs) and thermal

contributions to thermodynamic functions and activation parameters

were computed at the same level on the optimized structures, and

harmonic frequencies by using the rigid rotor/harmonic oscillator

approximation and the standard expressions for an ideal gas in the

canonical ensemble at 298.15 K and 1 atm. The transition states

were verified to have only one imaginary frequency and hence

correspond to a first-order saddle point on the potential energy

surface.

conductor polarizable continuum model (CPCM)³⁷as implemented

in Gaussian03, in which the solvent is represented by an infinite

dielectric medium characterized by the relative dielectric constant

of the bulk. A relative permittivity of 39.0 was assumed to simulate

DMF as solvent, and 7.58 for THF. After some tests, we observed

that for transition structures involving hydrogen shift it is necessary

to add an explicit sphere on the transferring atom in order to obtain

reliable results. Therefore, the solute cavity was built up with UA0

radii and explicitly placing an individual sphere on the hydrogen

of interest.

In some cases, the whole step path was traced by using the

intrinsic reaction coordinate (IRC) at the optimization level. The

IRC calculation started from the optimized transition structure and

followed the reaction path in both directions, toward the two minima

it connects.

Acknowledgment. E.G.-S. is an I3P-CSIC fellow. E.S. holds

a “Juan de la Cierva” contract (MEC, Spain). J.M.-C. thanks

CAM (Spain) for a grant (S/SAL-0275-2006) and Prof. Vasella

for the kind and useful information interchange.

In order to simulate the strong base, NH₂^-was selected instead

of H^-to avoid computational artifacts, since both species exhibit

a similar pK_avalue.³⁶

Supporting Information Available: NMR spectra for all new

compounds, general experimental methods, structural and stereo-

chemical assignments (Charts 1-4), theoretical scan of the PES

for the proton abstraction step to A1 (Figure 1), computed data in

the gas-phase and in solution (Tables 1-3), DFT-based study of

the formation of compounds 35, 38, and 47, complete ref 32, and

atomic coordinates for the computed structures. This material is

available free of charge via the Internet at http://pubs.acs.org.

Solvent effects have been taken into account by the self-

consistent reaction field (SCRF) method using the so-called

(35) (a) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P .v.

R. J. Comput. Chem. 1983, 4, 294. (b) Lynch, B. J.; Zhao, Y.; Truhlar, D.

G. J. Phys. Chem. A 2003, 107, 1384.

(36) (a) Buncel, E.; Menon, B. J. Am. Chem. Soc. 1977, 99, 4457. (b)

Buncel, E.; Menon, B. J. Organomet. Chem. 1977, 141, 1.

(37) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995.

JO701625A

8670 J. Org. Chem., Vol. 72, No. 23, 2007

Article Doi

Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3- ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3, trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4- dibromocyclohex-1-yl)-2

DOI: 10.1021/jo701625a

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