General protocols for the synthesis of C2-symmetric and asymmetric 2,8-disubstituted analogues of Troeger's base via efficient bromine-lithium exchanges of 2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine

Article abstract of DOI:10.1021/jo025823g

Methods for facile synthesis of symmetric and unsymmetric functionalized analogues of Troeger's base were developed with use of 2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (2) as the starting material. C₂-symmetric 2,8-disubstituted analogues of Troeger's base (4a-f) were synthesized via double bromine-lithium exchange of 2 followed by quench with electrophiles. Desymmetrization via single bromine-lithium exchange of 2, followed by quench with electrophiles, afforded asymmetric analogues of Troeger's base (6a-g). Further reaction of 2-bromo-8-(trimethylsilyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (6b) produced 7a-c via single bromine-lithium exchange and subsequent quench with electrophiles.

Full text of DOI:10.1021/jo025823g

Gen er a l P r otocols for th e Syn th esis of C2-Sym m etr ic a n d
Asym m etr ic 2,8-Disu bstitu ted An a logu es of Tr o1ger ’s Ba se via
Efficien t Br om in e-Lith iu m Exch a n ges of
2,8-Dibr om o-6H,12H-5,11-m eth a n od iben zo[b,f][1,5]d ia zocin e
J acob J ensen, J ohan Tejler, and Kenneth Wa¨rnmark*
Organic Chemistry 1, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden
Kenneth.Warnmark@orgk1.lu.se
Received April 15, 2002
Methods for facile synthesis of symmetric and unsymmetric functionalized analogues of Tro¨ger’s
base were developed with use of 2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (2)
as the starting material. C2-symmetric 2,8-disubstituted analogues of Tro¨ger’s base (4a -f) were
synthesized via double bromine-lithium exchange of 2 followed by quench with electrophiles.
Desymmetrization via single bromine-lithium exchange of 2, followed by quench with electrophiles,
afforded asymmetric analogues of Tro¨ger’s base (6a -g). Further reaction of 2-bromo-8-(trimeth-
ylsilyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (6b) produced 7a -c via single bromine-
lithium exchange and subsequent quench with electrophiles.
In tr od u ction
Tro¨ger’s base,1 2,8-dimethyl-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (1), is a chiral rigid molecule with
a concave shape (Figure 1). Analogues of Tro¨ger’s base
have been used as hosts in recognition phenomena,2 DNA
intercalation,3 enzyme inhibition4 and as ligands for
asymmetric catalysis.5,6 Although qualified for extensive
usage in many fields of chemistry and related sciences,
the number of synthesized analogues of Tro¨ger’s base has
hitherto been limited. The Tro¨ger’s base condensation
reaction of an aniline with formaldehyde, or its equiva-
lent, under acidic conditions, precludes the presence of
acid-sensitive functional groups. Anilines unsubstituted
in the 4-position do not form analogues of Tro¨ger’s base
in the condensation.7 More importantly, the Tro¨ger’s base
condensation reaction requires the aniline to be substi-
tuted with an electron-donating group.8 Only a few
exceptions to this latter prerequisite have been re-
ported.9,10 Therefore general strategies for the synthesis
of analogues of Tro¨ger’s base are lacking.
F IGURE 1. (a) ChemDraw representation of Tro¨ger’s base
(1). (b) Chem 3D representation of the energy-minimized
(Merck Molecular Force Field) Tro¨ger’s base.
Recently, we established conditions for anilines sub-
stituted with electron-withdrawing halogens in the 4-po-
sition to undergo the Tro¨ger’s base condensation reaction
to afford 2,8-dihalo-substituted analogues of Tro¨ger’s base
in good yields.11 To gain access to otherwise inaccessible
analogues of Tro¨ger’s base, we reckoned that bromine-
lithium exchange would provide the most facile and
general protocol for the preparation of substituted ana-
logues of Tro¨ger’s base. By exploiting the already fixed
positions of the bromines of 2,8-dibromo-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine (2, Scheme 1), func-
tional groups could be regioselectively introduced into the
2- and 8-positions of 2 via double bromine-lithium
exchange to the dilithiated analogue of Tro¨ger’s base 3
and subsequent quench with electrophiles. We herein
report a highly general protocol for the preparation of
C2-symmetric 2,8-difunctionalized analogues of Tro¨ger’s
base (4a -f) via efficient double bromine-lithium ex-
change of 2. Single bromine-lithium exchange should,
in addition, provide access to asymmetric functionalized
analogues of Tro¨ger’s base by desymmetrization of the
dissymmetric 2,8-dibromo analogue of Tro¨ger’s base 2.
(1) Tro¨ger, J . J . Prakt. Chem. 1887, 36, 225-245.
(2) Demeunynck, M.; Tatiboue¨t, A. Recent developments in Tro¨ger’s
base chemistry. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Cilchrist, T. L., Eds.; Pergamon: Oxford, UK, 1999; Vol. 11, pp 1-20.
(3) Bailly, C.; Laine, W.; Demeunynck, M.; Lhomme, J . Biochem.
Biophys. Res. Commun. 2000, 273, 681-685.
(4) J ohnson, R. A.; Gorman, R. R.; Wnuk, R. J .; Crittenden, N. J .;
Aiken, J . W. J . Med. Chem. 1993, 36, 3202-3206.
(5) Harmata, M.; Kahraman, M. Tetrahedron Asymmetry 2000, 11,
2875-2879.
(6) Blaser, H. U.; J alett, H. P.; Lottenbach, W.; Studer, M. J . Am.
Chem. Soc. 2000, 122, 12675-12682.
(7) Ha¨ring, M. Helv. Chim. Acta 1963, 46, 2970-2982.
(8) Webb, T. H.; Wilcox, C. S. J . Org. Chem. 1990, 55, 363-365.
(9) Cerrada, L.; Cudero, J .; Elguero, J .; Pardo, C. J . Chem. Soc.,
Chem. Commun. 1993, 1713-1714.
(10) Becker, D. P.; Finnegan, P. M.; Collins, P. W. Tetrahedron Lett.
1993, 34, 1889-1892.
(11) J ensen, J .; Wa¨rnmark, K. Synthesis 2001, 1873-1877.
10.1021/jo025823g CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/13/2002
6008
J . Org. Chem. 2002, 67, 6008-6014

Synthesis of 2,8-Disubstituted Analogues of Tro¨ger’s Base
SCHEME 1. Over a ll P r otocol for th e Syn th esis of C2-Sym m etr ic a n d Asym m etr ic An a logu es of Tr o1ger ’s
Ba se
TABLE 1. Op tim iza tion of th e Dou ble
In general, when having access to C2-symmetric starting
materials, desymmetrization has proven an efficient
means of synthesizing asymmetric compounds.12,13 Asym-
metric analogues are important because they would allow
for the construction of even larger libraries of Tro¨ger’s
base related building blocks with differentiated termini.
Asymmetric analogues of Tro¨ger’s base have hitherto
been almost inaccessible due to the lack of efficient
synthetic methods. Attempts to prepare asymmetric
analogues of Tro¨ger’s base by using two differently
substituted anilines in the Tro¨ger’s base condensation
reaction would give rise to a more or less statistical
mixture of three different analogues. In special cases,
however, asymmetrical analogues have been synthesized
by condensing two different anilines tethered with one
methylene unit.8 This method allowed for the synthesis
of asymmetric analogues of Tro¨ger’s base with an electron-
withdrawing group in only one of the aniline rings.
Facile access to asymmetric analogues of Tro¨ger’s base
would require efficient single bromine-lithium exchange
of 2 without concomitant double bromine-lithium ex-
change. Controlling single bromine-lithium exchange of
2,5-dibromopyrrole has been reported to be trivial.14,15
However, exclusive single bromine-lithium exchange of
2,6-dibromopyridine was only recently reported to pro-
ceed, by proper choice of solvent.16 In the present case,
the dilithiated compound 3 (Scheme 1) would carry one
negative charge in each of two discrete aromatic ring
systems. Hence, it might be expected that the balance of
controlling exclusive formation of the monolithiated
analogue of Tro¨ger’s base 5 (Scheme 1) would be rather
delicate because of the relatively low difference in stabil-
ity between 3 and 5, at least compared to the di- and
monoanion of the above-mentioned pyridine in which the
two repulsive charges of the dianion are localized in
proximity to each other. This would be expected to allow
for a more efficient repulsive interaction between the
charges, resulting in a larger difference in energy be-
tween the di- and monolithiated species.
Br om in e-Lith iu m Exch a n ge of 2 Accor d in g to th e
Rea ction in Sch em e 1 w ith H2O a s th e Electr op h ile
reaction timea (min)
0
2
5
10 15 20 25 30
yieldb (%) of 4a
82 89 88 85 85 87 76 67
a
b
In each case the n-BuLi was added over 5 min. Isolated yield
of chromatographically pure products.
Despite the anticipated difficulty in selectively gener-
ating the monolithiated species 5, we herein report a
highly general method for the synthesis of asymmetric
functionalized analogues of Tro¨ger’s base (6a -g, 7a -c)
via efficient single bromine-lithium exchange of 2
(Scheme 1).
Resu lts a n d Discu ssion
Op t im iza t ion of t h e Dou b le Br om in e-Lit h iu m
Exch a n ge. Initially the equivalents of n-BuLi required
to obtain complete double bromine-lithium exchange of
2 were determined by isolating the products obtained
after quenching the reaction with H2O.
With use of 1.1 equiv of n-BuLi per bromo atom, 35%
of the expected 2,8-dihydro analogue of Tro¨ger’s base,
compound 4a (Table 2), was isolated along with 15% of
the 2-bromo-8-hydro analogue 6a (Table 4), resulting
from single lithiation, when using not optimized reaction
conditions (Scheme 1). The use of 1.2 equiv of n-BuLi per
bromo atom produced solely 4a in 77% yield. Using
additional amounts of n-BuLi was not considered as
deprotonation, an undesired side reaction, of one of the
benzylic protons of Tro¨ger’s base has been reported under
comparable reaction conditions.17 The reaction was op-
timized with respect to the reaction time of the double
bromine-lithium exchange by isolating the products
resulting from different reaction times (Table 1). In the
interval 2-20 min the extent of the double bromine-
lithium exchange seemed more or less equal as judged
by the isolated yields of product. However, after 5 min
of reaction time the yield by crude product NMR was
above 98% and the isolated yield was 88% (corresponding
to 94% for each bromine-lithium exchange). Using 2 min
(12) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17.
(13) Magnusson, S. R. Tetrahedron 1995, 51, 2167-2213.
(14) Chen, W.; Cava, M. P. Tetrahedron Lett. 1987, 28, 6025-6026.
(15) Martina, S.; Enkelmann, V.; Wegner, G.; Schlu¨ter, A.-D.
Synthesis 1991, 613.
(16) Peterson, M. A.; Mitchell, J . R. J . Org. Chem. 1997, 62, 8237-
8239.
(17) Harmata, M.; Carter, K. W.; J ones, D. E.; Kahraman, M.
Tetrahedron Lett. 1996, 37, 6267-6270.
J . Org. Chem, Vol. 67, No. 17, 2002 6009

J ensen et al.
TABLE 2. In tr od u ction of Electr op h iles via Dou ble
Br om in e-Lith iu m Exch a n ge of 2 Accor d in g to th e
Rea ction in Sch em e 1
TABLE 3. Op tim iza tion of th e Sin gle Br om in e-Lith iu m
Exch a n ge of 2 Accor d in g to th e Rea ction in Sch em e 1
w ith H2O a s th e Electr op h ile
entry
electrophile
E
product
yielda (%)
solvent
equiv of n-BuLi
yielda (%) of 6a
1
2
3
4
5
6
7
8
H2O
TMSCl
DMF
PhCHO
CO2
Bu3SnCl
TsCN
BnBr
H
TMS
CHO
PhCH(OH)
CO2H
Bu3Sn
CN
4a
4b
4c
4d
4e
4f
88
89
54b
58
65c,d
71
d,e
f
THF
THF
THF
dichloromethane
THF/Et2O 3:8
THF/Et2O 3:8
1.3
1.2
1.05
1.2
1.2
1.1
57
71
59
b
82c
82c
a
b
Isolated yield of chromatographically pure products. Unre-
acted starting material. c Isolated yields of analytically pure
products.
Bn
a
b
Isolated yields of analytically pure products. Isolated yield
of chromatographically pure product. c In 1 mmol scale, isolated
d
as the mono-HCl salt. Using reverse addition for the quench with
the electrophile. e 7% of impure product (by NMR, HRMS, and IR)
was isolated. f 85% of 1,2-diphenylethane was isolated.
synthesized by adding the solution of 3 in THF to a
saturated solution of CO2 in THF at -78 °C; reverse
addition. The 2,8-bis(tributylstannyl) analogue 4f, entry
6, is seemingly quite stable to air, and might prove
efficient for introducing aromatic and heteroaromatic
substituents into the Tro¨ger’s base core via Stille cross-
coupling. Attempts to synthesize the analogue with two
cyano groups, entry 7, by the general procedure of adding
the electrophile to the reaction mixture resulted in a
complicated mixture. In situ generation of the dilithiated
compound 3 in the presence of the electrophile by
addition of n-BuLi to a solution of 2 and tosyl cyanide
was also unsuccessful. Therefore reverse addition as
described for the preparation of 4e above was attempted,
which nevertheless resulted in an unacceptable poor yield
of 2,8-dicyano-6H,12H-5,11-methanodibenzo[b,f][1,5]diazo-
cine, the identity of which was established by NMR,
HRMS, and IR. With benzyl bromide as an electrophile,
entry 8, a complicated mixture resulted and the only
major compound isolated was 1,2-diphenylethane (85%
calculated from benzyl bromide). This compound was
presumably formed by an initial bromine-lithium ex-
change of benzyl bromide and subsequent reaction (Wurtz
coupling) of the benzyllithium with benzyl bromide that
was in excess. In this case the bromine-lithium exchange
occurs faster than the desired electrophilic reaction.
Using benzyl chloride as the electrophile likewise failed
to produce the desired compound. To prevent the bro-
mine-lithium exchange from occurring prior to the
electrophilic reaction, it was considered worthwhile
examining the reaction with use of the corresponding
organomagnesium analogue of Tro¨ger’s base. All at-
tempts to form this compound by bromine-magnesium
exchange with isopropylmagnesium chloride, oxidative
addition with magnesium, and transmetallation of 3 with
MgBr2 failed in our hands.
of reaction time produced small amounts of 6a resulting
from incomplete dilithiation. Reaction times of 10 min
and more invariably allowed for the isolation and char-
acterization of different amounts of mono- and dibuty-
lated analogues of Tro¨ger’s base, presumably resulting
from Wurtz couplings between the formed n-butyl bro-
mide and the correspondingly formed lithiated analogue
of Tro¨ger’s base. In conclusion, using 5 min for the double
bromine-lithium exchange was found to be the optimal
conditions as lesser reaction times lead to incomplete
dilithiation. Prolonged reaction times resulted in the
formation of undesired byproducts by consumption of the
formed dilithiated analogue 3.
Syn th esis of C2-Sym m etr ic An a logu es. The opti-
mized conditions for the double bromine-lithium ex-
change were applied with different electrophiles in order
to investigate the generality of the method and to
synthesize new, previously inaccessible, analogues of
Tro¨ger’s base (Table 2).
The yields were generally good: 54%-89%, correspond-
ing to 73%-94% for each bromine-lithium exchange, with
the exceptions being entries 7 and 8. In some cases
minute amounts of products resulting from monodebro-
minated products were observed, presumably resulting
from monohydrolysis of the dilithiated 3 prior to the
intended double quench with electrophiles. The 2,8-
dihydro analogue of Tro¨ger’s base, compound 4a , entry
1, was the only compound previously reported,18 synthe-
sized in four steps in an overall yield of ca. 19%. In
comparison, the present methodology allowed for its
synthesis in only two steps from 4-bromoaniline in an
overall yield of 55%. The bis(trimethylsilyl) compound 4b
was formed in excellent yield and can be further deriva-
tized by either ipso-displacement19 or transition metal
mediated cross-coupling20 at a later stage if desired. In
the least favorable yields, synthesis of the diformyl (4c)
and the bis(hydroxyphenylmethyl) (4d ) analogues, en-
tries 3 and 4, no byproducts were produced in significant
amounts. The mixture of diastereomers constituting 4d
was not separated by column chromatography. The 2,8-
dicarboxyl analogue of Tro¨ger’s base 4e, entry 5, was
Op t im iza t ion of t h e Sin gle Br om in e-Lit h iu m
Exch a n ge. To perform efficient single bromine-lithium
exchange of 2, the effects on the yield of varying the
equivalents of n-BuLi and the solvent used were exam-
ined by isolating the 2-bromo-8-hydro analogue 6a after
quenching the reaction with H2O (Table 3).
The optimal conditions for the single bromine-lithium
exchange resulting in 6a were obtained with 1.1 equiv
of n-BuLi in a solvent mixture of THF/diethyl ether 3:8.
Neither the starting material 2 nor 4a resulting from
dilithiation was produced upon quench with water. When
1.2 equiv were used, a minute amount of 4a was
produced. Compound 2 was poorly soluble in Et2O, but
(18) Cooper, F. C.; Partridge, M. W. J . Chem. Soc. 1955, 991-994.
(19) Colvin, E. W. Silicon reagents in organic synthesis; Academic
Press: London, UK, 1988.
(20) Hiyama, T. In Metal-catalyzed Cross-coupling Reactions; Dieder-
ich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp
421-453.
6010 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of 2,8-Disubstituted Analogues of Tro¨ger’s Base
TABLE 4. In tr od u ction of Electr op h iles via Sin gle
Br om in e-Lith iu m Exch a n ge of 2 Accor d in g to th e
Rea ction in Sch em e 1
TABLE 5. In tr od u ction of Electr op h iles via
Br om in e-Lith iu m Exch a n ge of 6b
entry
electrophile
E
product
yielda (%)
entry
electrophile
E
product
yielda (%)
1
2
3
DMF
PhCHO
Bu3SnCl
CHO
PhCH(OH)
Bu3Sn
7a
7b
7c
63
1
2
3
4
5
6
7
8
H2O
TMSCl
DMF
PhCHO
CO2
Bu3SnCl
TsCN
BnBr
H
TMS
CHO
PhCH(OH)
CO2H
Bu3Sn
CN
6a
6b
6c
6d
6e
6f
82
68
71
62b
61c
70
60
d
84b
66
a
b
Isolated yield of analytically pure products. Isolated yield of
chromatographically pure product.
dilithio intermediate 3 with tosyl cyanide, which led to
a complicated mixture under similar reaction conditions,
indicating a higher reactivity of 3 compared to 5. In entry
8, using benzyl bromide as the electrophile resulted in
the same initial bromine-lithium exchange of benzyl
bromide as observed for the attempted synthesis of the
2,8-dibenzyl analogue of Tro¨ger’s base.
6g
Bn
a
b
Isolated yield of analytically pure products. Isolated yield of
chromatographically pure product. c In 1 mmol scale, isolated as
the mono-HCl salt. Using reverse addition for the quench with
d
the electrophile. 42% of 2 and 19% of 6a was isolated along with
unidentified components.
Syn th esis of An a logu es w ith Tw o Differ en t Elec-
tr op h iles. To further demonstrate the versatility of the
synthetic methods developed, a second bromine-lithium
exchange was performed on the trimethylsilyl-substituted
compound 6b. Subsequent quench with electrophiles
afforded previously inaccessible analogues of Tro¨ger’s
base 7a -c (Table 5).
This is thus a means of sequential bromine-lithium
exchange allowing for the introduction of two different
substituents, not bromine, into the Tro¨ger’s base core.
With this methodology the yields were good, and com-
parable to those of the formation of 4a -f and 6a -g. The
trimethylsilyl group not only tolerates the conditions of
n-BuLi, it also allows for further reaction as described
above.
readily soluble in the more polar THF. Most likely, the
dilithiated compound 3 was better solvated in THF than
in Et2O, because THF is a more strongly coordinating
solvent. We suggest that these differences in solubilizing
effects result in a larger difference in energy between
3and 5 in the solvent mixture THF/Et2O 3:8 than in THF.
Syn th esis of Asym m etr ic An a logu es. The optimized
conditions for single bromine-lithium exchange were
applied with different electrophiles in order to investigate
the generality of the method and to synthesize new,
previously inaccessible, analogues of Tro¨ger’s base (Table
4).
The same electrophiles as for the synthesis of C2
symmetrically substituted analogues of Tro¨ger’s base
above were used. The yields were generally good: 60-
82%, except again when using benzyl bromide, entry 8.
In all cases the yields were above the statistical distribu-
tion yield of 50%. The only previously reported method
for the synthesis of asymmetric analogues of Tro¨ger’s
base was a three-step synthetic sequence giving yields
ranging from 31% to 43%.8 The overall yields of the
present two-step procedure from 4-bromoaniline were in
the range of 38% to 52%, on comparable 1 mmol scale.
When quenching with the first electrophile, trimethylsilyl
chloride (Table 4, entry 2), the starting material 2 and
the doubly quenched bis(trimethylsilyl) analogue 4b were
produced, if the electrophile was added swiftly. Using 1
min for the addition eliminated this phenomenon, result-
ing in the desired 2-bromo-8-(trimethylsilyl) analogue 6b.
Consequently, as a general procedure, 1 min of addition
time of the electrophile was used for quenching 5 as
opposed to the quenching of 3, which was carried out
without delay. In addition, the synthesis of 6b was
carried out in two different scales as it was later used as
a starting material, thereby the effect of the scale on the
yield was examined. The difference in yield was consid-
ered insignificant, as the yield with 2 mmol of 2 was 70%
compared to 68% when 0.5 mmol of 2 was used. The
mixture of diastereomers constituting 6d was not sepa-
rated by column chromatography. The monocarboxylic
analogue 6e, entry 5, was prepared in the same manner
as the dicarboxylic acid 4e (Table 2, entry 5), namely by
reverse addition. With tosyl cyanide as the electrophile
the reaction proceeded without any apparent concomitant
formation of products resulting from nucleophilic attack
on the cyanide group once the product 6g was formed.
This was seemingly a difference from the quench of the
Con clu sion
In conclusion, using 2 as the starting material for
introducing electrophiles via the organolithium interme-
diates 3 and 5 allows for the facile preparation of C2-
symmetric and asymmetric 2,8-di- and monofunctional-
ized (apart from bromine) analogues of Tro¨ger’s base in
good to high yields. The method of single lithiation is also
a simple means of desymmetrization of an important
synthetic building block, giving access to important
asymmetric analogues of Tro¨ger’s base difficult to syn-
thesize by other means. With the sequential introduction
of electrophiles these protocols allow for a high degree of
choice of functional groups and differentiation of the
termini. Therefore this is a very versatile pathway to
complicated asymmetric analogues of Tro¨ger’s base.
Seemingly, there is a pronounced difference in stability
of the two species: dilithiated 3 and monolithiated 5. This
was observed as quench with tosyl cyanide proved
inefficient for 3 whereas 5 reacted in the anticipated way.
In addition, prolonged exposure of 2 to n-BuLi consumes
the formed 3 by reaction with the formed n-BuBr to afford
di- and monobutylated analogues of Tro¨ger’s base, ob-
servable after approximately 10 min. This was not the
case with 5 after exposure of 30 min. It should be possible
to further derivatize the synthesized new analogues of
Tro¨ger’s base to allow for the synthesis of highly complex
molecules for future usage in fields such as catalysis and
supramolecular chemistry.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under
argon atmosphere using syringe-septum cap techniques and
flame drying all glassware prior to use. TLC -analyses (Merck
J . Org. Chem, Vol. 67, No. 17, 2002 6011

J ensen et al.
60 F254 sheets) were visualized under UV light (254 nm).
Column chromatography (CC) was performed with silica gel
(Matrex 0.063-0.200 mm): diameter 6-6.5 cm; length 3.5-
10 cm; and fraction sizes 25 mL. Melting points (mp) were
determined in capillary tubes and were verified or corrected
with standard substances. Chemical shifts are given in ppm
relative to TMS, using the residual CHCl3 peaks at 7.26 (1H
NMR) and 77.16 (13C NMR) in CDCl3 and the residual MeOH
peaks at 3.31 (1H NMR) and 49.00 (13C NMR) in MeOH-d4 as
internal standards.21 For the numbering of atoms see Figure
1. Assignments were accomplished by coupling constants and
integrals. Elemental analyses were performed after CC or after
crystallization if required (according to NMR) by A. Kolbe,
Mikroanalytisches Laboratorium, Germany.
I, using 2 (188 mg, 0.50 mmol), 1.6 M n-BuLi (743 µL, 1.19
mmol), and DMF (109 mg, 1.49 mmol) as the electrophile. CC
(EtOAc (50%) in heptane) gave 74 mg (54%) of 4c: mp 160.0-
161.0 °C (EtOAc); Rf 0.12 (EtOAc (50%) in heptane); 1H NMR
(300 MHz, CDCl3) δ 4.32 (d, J ) 15.8 Hz, 2H), 4.35 (s, 2H,
H-13), 4.81 (d, J ) 17.0 Hz, 2H), 7.27 (d, J ) 9.2 Hz, 2H, H-4
and H-10), 7.48 (d, J ) 1.6 Hz, 2H, H-1 and H-7), 7. 07 (dd, J
) 8.3 Hz, J ) 1.9 Hz, 2H, H-3 and H-9), 9.84 (s, 2H, CHO);
13C NMR (100 MHz, CDCl3) δ 58.8 (2C, C-6 and C-12), 66.6
(1C, C-13), 125.8 (2C), 128.2 (2C), 129.2 (2C), 129.2 (2C), 132.7
(2C), 154.1 (2C), 191.1 (2C, CHO);. IR (KBr) 1683 cm-1 (Cd
O); HRMS (FAB+) calcd for C17H14N2O2 278.1055, found
278.1068. Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N,
10.07. Found: C, 73.31; H, 4.99; N, 9.89.
Ma ter ia ls. All chemicals were used as received from
commercial sources without further purification unless oth-
erwise stated, except for benzaldehyde and DMF which were
distilled prior to use. Anhydrous THF and Et2O were dried
and stored over 3 Å molecular sieves. n-BuLi was titrated prior
to use.22 Compound 2 was prepared in scales of 40-80 mmol
in 20-30% yields as previously described,11 with the exception
that TFA was added to the reaction mixture at 0 or -15 ïC.
All compounds were colorless crystals unless otherwise stated.
Dou ble Br om in e-Lith iu m Exch a n ge of 2 F ollow ed by
Rea ction w ith a n Electr op h ile: Gen er a l P r oced u r e I. To
a stirred solution of 2,8-dibromo-6H,12H-5,11-methanodibenzo-
[b,f][1,5]diazocine (2) (190 mg, 0.5 mmol) in THF (2 mL) at
2,8-Bis(h yd r oxyp h e n ylm e t h yl)-6H ,12H -5,11-m e t h -
a n od iben zo[b,f][1,5]d ia zocin e (4d ). 4d was prepared fol-
lowing general procedure I, using 2 (192 mg, 0.50 mmol), 1.6
M n-BuLi (756 µL, 1.21 mmol), and benzaldehyde (161 mg,
1.51 mmol) as the electrophile. CC (EtOAc (80%) in heptane)
gave 127 mg (58%) of 4d as a mixture of diastereomers: mp
83.0-84.5 °C; Rf 0.17 (EtOAc (40%) in heptane); 1H NMR (300
MHz, CDCl3) δ 3.45 (br s, 2H), 3.83-3.99 (m, 4H), 4.27-4.40
(m, 2H), 5.59-6.62 (m, 2H), 6.67-7.31 (m, 16H); HRMS (EI+)
calcd for C29H26N2O2 434.1994, found 434.2002. Anal. Calcd
for C29H26N2O2: C, 80.16; H, 6.03; N, 6.45. Found: C, 80.08;
H, 5.95; N, 6.27.
ï
2,8-Dica r boxyl-6H,12H-5,11-m eth a n od iben zo[b,f][1,5]-
d ia zocin e Hyd r o ch lor id e (4e). To a stirred solution of 2,8-
dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (2) (380
mg, 1.0 mmol) in THF (4 mL) at -78 °C was added dropwise
1.3 M n-BuLi in hexane (1.85 mL, 2.4 mmol) over 5 min. After
5 min the reaction mixture was transferred into a saturated
solution of CO2 in THF at -78 °C by means of a pipet at -78
°C. After filtration the solid was dissolved in methanol and
treated with a commercial solution of 4 M HCl in 1,4-dioxane
(1 mL). Concentration in vacuo and crystallization from
2-propanol (28 mL) gave 201 mg (65%) of 4e: decomposition
-78 C was added dropwise 1.6 M n-BuLi in hexane (750 µL,
1.2 mmol) over 5 min. After 5 min the electrophile (1.5 mmol)
was added swiftly and the reaction mixture was allowed to
reach room temperature over approximately 30 min. The
reaction was continued for 15 min additionally before water
(2 mL) was added. The layers were separated and the aqueous
layer was extracted with dichloromethane (3 × 10 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo and the crude product was purified by
CC with EtOAc/heptane as the eluent.
6H,12H-5,11-Meth a n od iben zo[b,f][1,5]d ia zocin e (4a ).
4a was prepared following general procedure I, using 2 (187
mg, 0.49 mmol), 1.6 M n-BuLi (740 µL, 1.18 mmol), and H2O
(2 mL) as the electrophile. CC (EtOAc (30%) in heptane) gave
97 mg (88%) of 4a : mp 136.5-137.0 °C (lit.18 mp 138-139 °C);
Rf 0.22 (EtOAc (40%) in heptane); 1H NMR (300 MHz, CDCl3)
δ 4.19 (d, J ) 16.5 Hz, 2H), 4.34 (s, 2H, H-13), 4.71 (d, J )
16.6 Hz, 2H), 6.89-7.00 (m, 4H), 7.12-7.19 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 58.8 (2C, C-6 and C-12), 66.9 (1C, C-13),
124.1 (2C), 125.3 (2C), 127.1 (2C), 127.5 (2C), 128.0 (2C), 148.2
(2C); HRMS (EI+) calcd for C15H14N2 222.1157, found 222.1158.
Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found:
C, 80.93; H, 6.35; N, 12.47.
1
above 220 °C (2-propanol); H NMR (300 MHz, MeOH-d4) δ
4.62 (d, J ) 17.1 Hz, 2H), 4.91 (s, 2H, H-13), 5.06 (d, J ) 16.8
Hz, 2H), 7.51 (d, J ) 8.4 Hz, 2H, H-3 and H-9 or H-4 and H-10),
7.85 (s, 2H, H-1 and H-7), 7.99 (d, J ) 8.4 Hz, 2H, H-3 and
H-9 or H-4 and H-10); 13C NMR (75 MHz, MeOH-d4) δ 58.2
(2C, C-6 and C-12), 67.9 (1C, C-13), 125.8 (2C), 126.5 (2C),
130.5 (2C), 131.2 (2C), 131.5 (2C), 145.4 (2C), 168.1 (2C, CO2H);
IR (KBr) 2966 (br, O-H) 1697 (CdO) cm-1; HRMS (EI+) calcd
for C17H14N2O2 310.0954, found 310.0965. Anal. Calcd for
C
17H15ClN2O2: C, 58.88; H, 4.36; N, 8.08. Found: C, 59.04; H,
4.42; N, 7.97.
2,8-Bis(tr ibu tylsta n n yl)-6H,12H-5,11-m eth a n od iben zo-
[b,f][1,5]d ia zocin e (4f). 4f was prepared following general
procedure I with the addition that the crude product was
redissolved in Et2O (10 mL) and stirred for 1 h with a 10%
aqueous solution of KF. The white solid was filtered off and
after separation of the two layers the aqueous layer was
extracted with DCM (3 × 10 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo and
the crude product was purified by CC. Using 2 (193 mg, 0.51
mmol), 1.6 M n-BuLi (762 µL, 1.22 mmol), and tributylstannyl
chloride (410 µL, 1.52 mmol) as the electrophile. CC (EtOAc
(0-20%) in heptane) gave 289 mg (71%) of 4f as a colorless
oil: Rf 0.42 (EtOAc (20%) in heptane); 1H NMR (300 MHz,
CDCl3) δ 0.84-0.89 (m, 18H, 6 × CH3), 0.96-1.01 (m, 12H, 6
× CH2), 1.27-1.34 (m, 12H, 6 × CH2), 1.45-1.53 (m, 12H, 6
× CH2), 4.19 (d, J ) 16.7 Hz, 2H), 4.31 (s, 2H, H-13), 4.71 (d,
2H, J ) 16.6 Hz), 6.97 (s, 2H, H-1 and H-7), 7.10 (d, 2H, J )
7.8 Hz, H-3 and H-9 or H-4 and H-10), 7.24 (d, 2H, J ) 7.9
Hz, H-3 and H-9 or H-4 and H-10); 13C NMR (75 MHz, CDCl3)
δ 9.7 (6C), 13.8 (6C), 27.5 (6C), 29.2 (6C), 58.6 (2C, C-6 and
C-12), 66.8 (1C, C-13), 124.9 (2C), 127.8 (2C), 135.1 (2C), 135.4
(2C), 136.8 (2C), 148.3 (2C); HRMS (FAB+) calcd for C39H67N2-
120Sn2 (M + H+) 803.3348, found 803.3349. Anal. Calcd for
2,8-Bis(t r im et h ylsilyl)-6H,12H-5,11-m et h a n od ib en zo-
[b,f][1,5]d ia zocin e (4b). 4b was prepared following general
procedure I, using 2 (189 mg, 0.50 mmol), 1.6 M n-BuLi (745
µL, 1.19 mmol), and trimethylsilyl chloride (152 mg, 1.4 mmol),
which was dried over CaH2 and freshly distilled under argon,
as the electrophile. CC (EtOAc (20%) in heptane) gave 152 mg
(89%) of 4b: mp 172.5-173.0 °C; Rf 0.24 (EtOAc (20%) in
heptane); 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 18H, 6 × CH3),
4.22 (d, J ) 16.7 Hz, 2H), 4.32 (s, 2H, H-13), 4.73 (d, J ) 16.6
Hz, 2H), 7.06 (d, J ) 0.8 Hz, 2H, H-1 and H-7), 7.14 (d, J )
7.9 Hz, 2H, H-4 and H-10), 7.32 (dd, J ) 7.9, 0.8 Hz, 2H, H-3
and H-9); 13C NMR (75 MHz, CDCl3) δ -0.9 (6C, 6 × CH3),
58.6 (2C, C-6 and C-12), 66.8 (1C, C-13), 124.7 (2C), 127.4 (2C),
132.3 (2C), 132.4 (2C), 135.7 (2C), 149.0 (2C); HRMS (FAB+)
calcd for C21H30N2Si2 366.1948, found 366.1941. Anal. Calcd
for C21H30N2Si2: C, 68.79; H, 8.25; N, 7.64. Found: C, 68.86;
H,8.22; N, 7.69.
2,8-Difor m yl-6H ,12H -5,11-m et h a n od ib en zo[b,f][1,5]-
d ia zocin e (4c). 4c was prepared following general procedure
(21) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J . Org. Chem. 1997,
62, 7512-7515.
(22) Suffert, J . J . Org. Chem. 1989, 54, 509-510.
6012 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of 2,8-Disubstituted Analogues of Tro¨ger’s Base
39H66N2Sn2: C, 58.52; H, 8.31; N, 3.50. Found: C, 58.45; H,
C
11H); HRMS (FAB+) calcd for C22H1979BrN2O 406.0681, found
406.0673. Anal. Calcd for C22H19BrN2O: C, 64.87; H, 4.70; N,
6.98. Found: C, 64.94; H, 4.82; N, 6.79.
8.22; N, 3.56.
Sin gle Br om in e-Lith iu m Exch a n ge of 2 F ollow ed by
Rea ction w ith a n Electr op h ile: Gen er a l P r oced u r e II.
To a stirred solution of 2,8-dibromo-6H,12H-5,11-methanodi-
benzo[b,f][1,5]diazocine (2) (190 mg, 0.5 mmol) in THF (1.5 mL)
and Et2O (4 mL) at -78 °C was added dropwise 1.6 M n-BuLi
in hexane (344 µL, 0.55 mmol) over 2 min. After 5 min the
electrophile (0.75 mmol) was added dropwise over 1 min and
the reaction mixture was allowed to reach room temperature
over approximately 30 min. The reaction was continued for
15 min additionally before water (2 mL) was added. The layers
were separated and the aqueous layer was extracted with
dichloromethane (3 × 10 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo and
the crude product was purified by CC with EtOAc/heptane as
the eluent.
2-Br om o-8-ca r boxyl-6H,12H-5,11-m eth a n od iben zo[b,f]-
[1,5]d ia zocin e Hyd r och lor id e (6e). To a stirred solution of
2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (2)
(378 mg, 1.0 mmol) in THF (3 mL) and Et2O (8 mL) at -78 °C
was added dropwise 1.6 M n-BuLi in hexane (684 µL, 1.09
mmol) over 2 min. After 5 min the reaction mixture was
transferred into a saturated solution of CO2 in THF at -78
°C by means of a pipet at -78 °C. The reaction mixture was
concentrated in vacuo and the solid was dissolved in methanol
and treated with a commercial solution of 4 M HCl in 1,4-
dioxane (1 mL). Concentration in vacuo and crystallization
from 2-propanol (9 mL) gave 233 mg (61%) of 6e with
decomposition above 200 °C (2-propanol): 1H NMR (300 MHz,
MeOH-d4) δ 4.43-4.55 (m, 2H), 4.81-5.05 (m, 4H), 7.34-7.51
(m, 4H), 7.78-7.79 (m, 1H), 7.90-7.95 (m, 1H); 13C NMR (75
MHz, MeOH-d4) δ 58.0 (1C), 58.6 (1C), 67.9 (1C), 122.2 (1C),
125.6 (1C), 126.0 (1C), 127.3 (1C), 130.0 (1C), 130.4 (1C), 130.4
(1C), 131.0 (1C), 131.7 (1C), 132.9 (1C), 140.5 (1C), 148.4 (1C),
168.5 (1C, CO2H); IR (KBr) 2829 (br, O-H), 1712, 1692, 1682
cm-1; HRMS (FAB+) calcd for C16H1379BrN2O2 344.0160, found
344.0164. Anal. Calcd for C16H14BrClN2O2: C, 50.35; H, 3.70;
N, 7.34. Found: C, 50.28; H, 3.85; N, 7.45.
2-Br om o-8-(t r ib u t ylst a n n yl)-6H ,12H -5,11-m et h -a n o-
d iben zo[b,f][1,5]d ia zocin e (6f). 6f was prepared following
general procedure II with the addition that the crude product
was redissolved in Et2O (10 mL) and stirred for 1 h with a
10% aqueous solution of KF. The white solid was filtered off
and after separation of the two layers, the aqueous layer was
extracted with DCM (3 × 10 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo and
the crude product was purified by CC, using 2 (192 mg, 0.51
mmol), 1.3 M n-BuLi (427 µL, 0.56 mmol), and tributylstannyl
chloride (206 µL, 0.76 mmol) as the electrophile. CC (EtOAc
(10-20%) in heptane) gave 210 mg (70%) of 6f: mp 55.0-56.0
°C; Rf 0.26 (EtOAc (20%) in heptane); 1H NMR (300 MHz,
CDCl3) δ 0.85-0.90 (m, 9H, 3 × CH3), 0.97-1.02 (m, 6H),
1.27-1.35 (m, 6H), 1.47-1.54 (m, 6H), 4.10-4.34 (m, 4H),
4.62-4.73 (m, 2H), 6.96 (s, 1H), 7.01-7.08 (m, 3H), 7.24-7.28
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 9.7 (3C), 13.8 (3C), 27.5
(3C), 29.2 (3C), 58.4 (1C), 58.8 (1C), 66.8 (1C), 116.6 (1C), 124.7
(1C), 127.0 (1C), 127.3 (1C), 129.9 (1C), 130.4 (1C), 130.5 (1C),
135.0 (1C), 135.6 (1C), 137.3(1C), 147.5 (1C), 147.8 (1C); HRMS
(FAB+) calcd for C27H4079BrN2120Sn (M + H+) 591.1397, found
591.1411. Anal. Calcd for C27H39BrN2Sn: C, 54.94; H, 6.66;
N, 4.75. Found: C, 54.88; H, 6.68; N, 4.73.
2-B r o m o -6H ,12H -5,11-m e t h a n o d i b e n z o [b ,f][1,5]-
d ia zocin e (6a ). 6a was prepared following general procedure
II, using 2 (188 mg, 0.49 mmol), 1.3 M n-BuLi (419 µL, 0.54
mmol), and H2O (2 mL) as the electrophile. CC (EtOAc (40%)
in heptane) gave 141 mg (82%) of 6a : mp 123.5-125.0 °C; Rf
1
0.20 (EtOAc (40%) in heptane); H NMR (300 MHz, CDCl3) δ
4.10-4.18 (m, 2H), 4.23-4.34 (m, 2H), 4.62-4.72 (m, 2H),
6.92-7.26 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 58.5 (1C), 58.8
(1C), 66.9 (1C), 116.6 (1C), 124.3(1C), 125.2 (1C), 126.9 (1C),
127.1 (1C), 127.64 (1C), 127.65 (1C), 129.8 (1C), 130.2 (1C),
130.5 (1C), 147.3 (1C), 147.8 (1C); HRMS (FAB+) calcd for
C15H1379BrN2 300.0262, found 300.0264. Anal. Calcd for C15H13
-
BrN2: C, 59.82; H, 4.35; N, 9.30. Found: C, 59.70; H, 4.40; N,
9.22.
2-B r o m o -8-(t r im e t h y ls ily l)-6H ,12H -5,11-m e t h a n o -
d iben zo[b,f][1,5]d ia zocin e (6b). 6b was prepared following
general procedure II, using 2 (187 mg, 0.49 mmol), 1.3 M
n-BuLi (416 µL, 0.54 mmol), and trimethylsilyl chloride (93
µL, 0.74 mmol) as the electrophile. CC (EtOAc (20%) in
heptane) gave 125 mg (68%) of 6b: mp 140.0-141.0 °C; Rf
1
0.12 (EtOAc (20%) in heptane); H NMR (300 MHz, CDCl3) δ
0.22 (s, 9H, 3 × CH3), 4.12-4.20 (m, 2H), 4.23-4.35 (m, 2H),
4.63-4.74 (m, 2H), 7.02-7.06 (m, 3H), 7.10-7.13 (m, 1H),
7.25-7.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ -1.0 (3C,-
CH3), 58.4 (1C), 58.8 (1C), 66.8 (1C), 116.6 (1C), 124.5 (1C),
126.9 (1C), 127.0 (1C), 129.8 (1C), 130.3 (1C), 130.5 (1C), 132.2
(1C), 132.6 (1C), 136.0 (1C),147.4 (1C), 148.6 (1C); HRMS
(FAB+) calcd for C18H2179BrN2Si 372.0657, found 372.0657.
Anal. Calcd for C18H21BrN2Si: C, 57.90; H, 5.67; N, 7.50.
Found: C, 58.10; H, 5.62; N, 7.41.
2-Br om o-8-for m yl-6H ,12H -5,11-m et h a n od ib en zo[b,f]-
[1,5]d ia zocin e (6c). 6c was prepared following general
procedure II, using 2 (193 mg, 0.51 mmol), 1.3 M n-BuLi (430
µL, 0.56 mmol), and DMF (59 µL,0.76 mmol) as the electro-
phile. CC (EtOAc (50-60%) in heptane) gave 119 mg (71%) of
6c: mp 204.0-205.5 °C; Rf 0.16 (EtOAc (50%) in heptane); 1H
NMR (300 MHz, CDCl3) δ 4.16-4.23 (m, 2H), 4.28 (s, 2H,
H-13), 4.67-4.75 (m, 2H), 7.00-7.05 (m, 2H), 7.22-7.29 (m,
2-Br om o-8-cyan o-6H,12H-5,11-m eth an odiben zo[b,f][1,5]-
d ia zocin e (6g). 6g was prepared following general procedure
II, using 2 (192 mg, 0.51 mmol), 1.3 M n-BuLi (427 µL, 0.56
mmol), and tosyl cyanide (137 mg, 0.76 mmol) in THF (1 mL)
as the electrophile. CC (EtOAc (40%) in heptane) gave 99 mg
(60%) of 6f: mp 203.0-205.0 °C; Rf 0.18 (EtOAc (40%) in
heptane); 1H NMR (300 MHz, CDCl3) δ 4.10-4.19 (m, 2H),
4.26 (d, J ) 1.2 Hz, 2H), 4.63-4.71 (m, 2H), 6.99-7.06 (m,
2H), 7.16-7.30 (m, 3H), 7.41-7.44 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 58.3 (1C), 58.5 (1C), 66.6 (1C), 107.5 (1C), 117.1 (1C),
118.8 (1C), 125.9 (1C), 126.9 (1C), 129.1 (1C), 129.5 (1C), 129.8
(1C), 131.0 (1C), 131.2 (1C), 131.5 (1C), 146.6 (1C), 152.7 (1C);
2H), 7.447-7.453 (m, 1H), 7.66-7.69 (m, 1H), 9.83 (s, 1H); 13
C
NMR (75 MHz, CDCl3) δ 58.6 (1C), 58.6 (1C), 66.7 (1C), 117.0
(1C), 125.7 (1C), 126.9 (1C), 128.3 (1C), 128.9 (1C), 129.3 (1C),
129.7 (1C), 129.8 (1C), 130.9 (1C), 132.6 (1C), 146.8 (1C), 154.3
(1C), 191.1 (1C); IR (KBr) 1697, 1680, 1668 cm-1; HRMS
(FAB+) calcd for C16H1379BrN2O 328.0211, found 328.0214.
Anal. Calcd for C16H13BrN2O: C, 58.38; H, 3.98; N, 8.51.
Found: C, 58.50; H, 4.11; N, 8.43.
IR (KBr) 2222 cm-1 (CN); HRMS (FAB+) calcd for C16H12
-
-
79BrN3 325.0215, found 325.0199. Anal. Calcd for C16H12
BrN3: C, 58.91; H, 3.71; N, 12.88. Found: C, 59.07; H, 3.69;
N, 12.75.
2-B r o m o -8-(h y d r o x y p h e n y lm e t h y l)-6H ,12H -5,11-
m eth a n od iben zo[b,f][1,5]d ia zocin e (6d ). 6d was prepared
following general procedure II, using 2 (189, 0.50 mmol), 1.3
M n-BuLi (421 µL, 0.55 mmol), and benzaldehyde (76 µL, 0.75
mmol) as the electrophile. CC (EtOAc (70-80%) in heptane)
gave 125 mg (62%) of 6d as a mixture of diastereomers: mp
98.5-100.0 °C (heptane); Rf 0.42 (EtOAc (80%) in heptane);
1H NMR (300 MHz, CDCl3) δ 2.92 (br s, 1H), 3.99-4.17 (m,
4H), 4.52-4.57 (m, 2H), 5.66-5.67 (m, 1H), 6.84-7.32 (m,
Sin gle Br om in e-Lith iu m Exch a n ge of 6b F ollow ed by
Rea ction w ith a n Electr op h ile: 2-F or m yl-8-(tr im eth yl-
silyl)-6H,12H-5,11-m eth an odiben zo[b,f][1,5]diazocin e (7a).
7a was prepared following general procedure I, using 6b (187
mg, 0.50 mmol), 1.3 M n-BuLi (462 µL, 0.60 mmol), and DMF
(58 µL, 0.75 mmol) as the electrophile. CC (EtOAc (30%) in
heptane) gave 101 mg (63%) of 7a : mp 214.0-215.0 °C; Rf
1
0.18 (EtOAc (40%) in heptane); H NMR (300 MHz, CDCl3) δ
J . Org. Chem, Vol. 67, No. 17, 2002 6013

J ensen et al.
0.20 (s, 9H, 3 × CH3), 4.24-4.37 (m, 4H), 4.72-4.80 (m, 2H),
7.05 (d, J ) 0.5 Hz, 1H), 7.13 (d, J ) 7.9 Hz, 1H), 7.25-7.34
(m, 2H), 7.45, (d, J ) 1.6 Hz, 1H), 7.66-7.69 (dd, J ) 8.3, 1.9
Hz, 1H), 9.83 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3) δ -1.0
(3C), 58.5 (1C), 58.9 (1C), 66.8 (1C), 124.6 (1C), 125.8 (1C),
126.9 (1C), 128.7 (1C), 128.7 (1C), 129.5 (1C), 132.2 (1C), 132.5
(1C), 132.7 (1C), 136.2 (1C), 148.4 (1C), 154.9 (1C), 191.2 (1C);
IR (KBr) 1680 cm-1 (CdO); HRMS (FAB+) calcd for C19H22N2-
OSi 322.1501, found 322.1495. Anal. Calcd for C19H22N2OSi:
C, 70.77; H, 6.88; N, 8.69. Found: C, 70.64; H, 6.86; N, 8.54.
2-(H yd r oxyp h en ylm et h yl)-8-(t r im et h ylsilyl)-6H ,12H -
5,11-m eth a n od iben zo[b,f][1,5]d ia zocin e (7b). 7b was pre-
pared following general procedure I, using 6b (184 mg, 0.49
mmol), 1.3 M n-BuLi (455 µL, 0.59 mmol), and benzaldehyde
(75 µL, 0.74 mmol) as the electrophile. CC (EtOAc (60%) in
heptane) gave 165 mg (84%) of 7b as a mixture of diastereo-
mers. An analytically pure sample was obtained by CC: mp
99.5-101.0 °C; Rf 0.25 (EtOAc (80%) in heptane); 1H NMR (300
MHz, CDCl3) δ 0.23-0.24 (m, 9H, 3 × CH3), 3.22 (br s, 1H,
OH), 4.07-4.21 (m, 4H), 4.54-4.66 (m, 2H), 5.67 (br s, 1H,
CH), 6.85-7.37 (m, 11H); HRMS (FAB+) calcd for C25H28N2-
OSi 400.1971, found 400.1977. Anal. Calcd for C25H28N2OSi:
C, 74.96; H, 7.05; N, 6.99. Found: C, 74.88; H, 7.11; N, 6.84.
2-(Tr ib u t ylst a n n yl)-8-(t r im e t h ylsilyl)-6H ,12H -5,11-
m eth a n od iben zo[b,f][1,5]d ia zocin e (7c). 7c was prepared
following general procedure I with the addition that the crude
product was redissolved in Et2O (10 mL) and stirred for 1 h
with a 10% aqueous solution of KF. The white solid was
filtered off and after separation of the two layers, the aqueous
layer was extracted with DCM (3 × 10 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated
in vacuo and the crude product was purified by CC, using 6b
(187 mg, 0.50 mmol), 1.3 M n-BuLi (424 µL, 0.55 mmol), and
tributylstannyl chloride (204 µL, 0.75 mmol) as the electro-
phile. CC (EtOAc (15%) in heptane) gave 192 mg (66%) of 7c
as a colorless oil: Rf 0.24 (EtOAc (20%) in heptane); 1H NMR
(300 MHz, CDCl3) δ 0.23 (s, 9H, 3 × Si-CH3), 0.87-0.91 (m,
9H, 3 × Sn-CH3), 0.98-1.04 (m, 6H), 1.29-1.37 (m, 6H), 1.49-
1.56 (m, 6H), 4.23 (dd, J ) 16.7, 4.0 Hz, 2H), 4.33 (s, 2H), 4.74
(d, J ) 16.6 Hz, 2H), 6.99 (d, J ) 0.6 Hz, 1H), 7.06-7.17 (m,
3H), 7.25-7.35 (m, 2H); 13C NMR (75 MHz, CDCl3) δ -0.9 (3C),
9.7 (3C), 13.8 (3C), 27.5 (3C), 29.2 (3C), 58.6 (1C), 58.7 (1C),
66.8 (1C), 124.7 (1C), 124.9 (1C), 127.5 (1C), 127.8 (1C), 132.3
(1C), 132.3 (1C), 135.1 (1C), 135.4 (1C), 135.5 (1C), 136.8 (1C),
148.3 (1C), 149.2 (1C); HRMS (FAB+) calcd for C30H47N2Si-
120Sn (M - H+) 583.2531, found 583.2507. Anal. Calcd for
C
30H48N2SiSn: C, 61.75; H, 8.29; N, 4.80. Found: C, 61.62;
H, 8.21; N, 4.88.
Ack n ow led gm en t. We thank the Swedish Research
Council as well as the Crafoord Foundation, the Lars-
J ohan Hierta Foundation, the Magn. Bergvall Founda-
tion, and the Royal Physiographic Society for generous
grants.
Note Ad d ed a fter ASAP . In the version posted on
J uly 13, 2002, there were errors throughout the number-
ing of the references. The corrected version was posted
on J uly 22, 2002.
J O025823G
6014 J . Org. Chem., Vol. 67, No. 17, 2002