Synthesis of medium-bridged twisted lactams via cation-π control of the regiochemistry of the intramolecular Schmidt reaction

Article abstract of DOI:10.1021/jo902574m

(Chemical Equation Presented) Medium-bridged twisted amides can be synthesized by the intramolecular Schmidt reaction of 2-azidoalkyl ketones. In these reactions, the regiochemistry of the Schmidt reaction is diverted into a typically disfavored pathway b

Full text of DOI:10.1021/jo902574m

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Synthesis of Medium-Bridged Twisted Lactams via Cation-π Control of
the Regiochemistry of the Intramolecular Schmidt Reaction
ꢀ
Michal Szostak, Lei Yao, and Jeffrey Aube*
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall,
Room 4070, Lawrence, Kansas 66045-7852
jaube@ku.edu
Received December 4, 2009
Medium-bridged twisted amides can be synthesized by the intramolecular Schmidt reaction of
2-azidoalkyl ketones. In these reactions, the regiochemistry of the Schmidt reaction is diverted into a
typically disfavored pathway by the presence of an aromatic group at the R-position adjacent to the
ketone, which stabilizes the predominantly reactive conformation of the azidohydrin intermediate by
engaging in a nonbonded cation-π interaction with the positively charged diazonium cation. This
results in the rarely observed rearrangement of the C-C bond distal to the azidoalkyl chain. This
reaction pathway also requires the azide-containing tether to be situated in the axial orientation in the
key azidohydrin intermediate. Examination of the effect of substitution of aromatic rings on the
regiochemistry of the Schmidt reaction shows an increase in the migratory selectivity with more electron-
rich aromatic groups. The selectivity is lower when an electron-withdrawing substituent is placed on the
aromatic ring. The ability of cation-π interactions to act as a controlling element decreases when Lewis
acids coordinate to substituents on the aromatic ring. The developed version of the Schmidt reaction
provides a direct access to a family of medium-bridged twisted amides with a [4.3.1] bicyclic system,
compounds which are very difficult to access with use of other currently available methods.
SCHEME 1
Introduction
The intramolecular Schmidt reaction effectively permits
the synthesis of ring systems featuring a nitrogen atom at the
ring fusion position.1 This sequence is a valuable tool in the
preparation of natural products2 and other biologically
relevant compounds.3 In most applications of this chemi-
stry, ketones4 and carbocations5 (typically generated from
tertiary alcohols and olefins) are employed as electro-
philic components; however, applications of epoxides,2j,k
alkynes,3e,f enones,6 sulfonium ions,2r and boranes2s,t have
also appeared in the last two decades.
of the azide into the proximal C-C bond of the reactive
electrophile would give a fused structure (path a), while the
insertion into the distal C-C bond would give a bridged
system (path b). In the vast majority of cases, products
resulting from the migration of the proximal C-C bond
(path a) have been observed.
Two regiochemical outcomes can be envisioned from
2-azidoalkyl ketone substrates (Scheme 1).4a Formal insertion
*To whom correspondence should be addressed. Phone: 1.785.864.4496.
Fax: 1.785.864.5326.
(1) For recent reviews, see: (a) Lang, S.; Murphy, J. A. Chem. Soc. Rev.
2006, 35, 146–156. (b) Nyfeler, E.; Renaud, P. Chimia 2006, 60, 276–284. (c)
In a related reaction, Pearson and co-workers5b obtained a
ca. 2:1 mixture of bridged bicyclic enamines upon treatment
of 3-(2-azidoethyl)-1-phenylcyclopentanol with protic and
ꢀ
€
Grecian, S.; Aube, J. Organic Azides: Syntheses and Applications; Brase, S.,
Banert, K., Eds.; John Wiley and Sons: Hoboken, NJ, 2009.
DOI: 10.1021/jo902574m
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Published on Web 01/22/2010
J. Org. Chem. 2010, 75, 1235–1243 1235
2010 American Chemical Society

Szostak et al.
JOCArticle
Lewis acids (Scheme 2, top). This reaction proceeds via an R-
amino carbocation that undergoes rapid deprotonation to
SCHEME 2
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F.; Dangelo, J. J. Org. Chem. 1993, 58, 2933–2935. (b) Smith, B. T.; Wendt, J. A.;
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Aube, J. Org. Lett. 2002, 4, 2577–2579. (c) Wrobleski, A.; Sahasrabudhe, K.;
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Aube, J. J. Am. Chem. Soc. 2002, 124, 9974–9975. (d) Gracias, V.; Zeng, Y. B.;
Desai, P.; Aube, J. Org. Lett. 2003, 5, 4999–5001. (e) Golden, J. E.; Aube, J.
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ꢀ
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Chem. Soc. 2005, 127, 15712–15713. (g) Iyengar, R.; Schildknegt, K.; Morton,
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Ribelin, T.; Aube, J. Org. Lett. 2009, 11, 4140–4142. (i) Pearson, W. H.; Fang, W.
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afford the twisted enamine-containing products shown. More
recently, Tani and Stoltz7 demonstrated that a structurally
related β-substituted azidoalkyl ketone provided a ca. 3:1
mixture of bridged amides resulting from the migration of
both R-keto bonds (Scheme 2, bottom). Recrystallization
allowed for isolation of 2-quinuclidone as its protonated
derivative in 38% yield. This sequence was particularly note-
worthy because it permitted the isolation and characterization
of the iconic twisted amide for the first time after more than
60 years of attempts to prepare this compound,8 confirming
that the loss of N2 is a powerful driving force for the
formation of unstable ring systems.
Our group has been interested in properties of medium-
bridged twisted amides bearing a carbonyl group at the shortest
one-carbon bridge in bicyclic ring systems.9 Similar to 2-qui-
nuclidone, these compounds contain heavily pyramidalized
nitrogen atoms, and display properties divergent from planar
amides. We have reported unprecedented cleavage reactions of
the C-N bond adjacent to the bridged amide bond in a series of
tricyclic and bicyclic twisted amides.10 We have also examined
the hydrolytic behavior of one-carbon bridged lactams, demon-
strating that these compounds offer superior levels of stability
compared to the twisted amides based on the 2-quinuclidone
scaffold.11 Since one-carbon bridged amides are significantly
twisted, as evidenced by their substantial twist values of ca. 50°
as well as their spectral and chemical properties,10-12 these
compounds can provide a useful platform for investigation of
biological and chemical properties of unconventional amide
linkages. For example, bridged lactams could facilitate the study
of nonplanar amide bonds that are commonly encountered
during cis/trans isomerization of amides in peptides.13 Non-
planar amides have also been proposed as high-energy inter-
mediates in enzymatic cleavage reactions of peptides.14 In
addition, bridged amides can be used to experimentally examine
(3) For selected examples, see: (a) Pearson, W. H.; Gallagher, B. M.
ꢀ
Tetrahedron 1996, 52, 12039–12048. (b) Badiang, J. G.; Aube, J. J. Org.
Chem. 1996, 61, 2484–2487. (c) Reddy, D. S.; Vander Velde, D.; Aube, J. J.
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Org. Chem. 2004, 69, 1716–1719. (d) Fenster, E.; Rayabarapu, D. K.; Zhang,
M.; Mukherjee, S.; Hill, D.; Neuenswander, B.; Schoenen, F.; Hanson, P. R.;
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Aube, J. J. Comb. Chem. 2008, 10, 230–234. (e) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260–11261. (f) Batchu, V. R.;
Barange, D. K.; Kumar, D.; Sreekanth, B. R.; Vyas, K.; Reddy, E. A.; Pal,
M. Chem. Commun. 2007, 1966–1968. (g) Dong, H.; Shen, M.; Redford, J. E.;
Stokes, B. J.; Pumphrey, A. L.; Driver, T. G. Org. Lett. 2007, 9, 5191–5194.
(h) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367–3370. (i) Rostami, A.;
Wang, Y.; Arif, A. M.; McDonald, R.; West, F. G. Org. Lett. 2007, 9, 703–
706.
ꢀ
(4) (a) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc. 1995,
117, 10449-10459. For reactions with ketals and enol ethers, see: (b) Mossman,
ꢀ
C. J.; Aube, J. Tetrahedron 1996, 52, 3403-3408. For intermolecular Schmidt
ꢀ
reactions with ketones, see: (c) Aube, J.; Milligan, G. L.; Mossman, C. J. J. Org.
Chem. 1992, 57, 1635-1637. For in situ tethering utilizing azido alcohols, see:
ꢀ
(d) Gracias, V.; Milligan, G. L.; Aube, J. J. Am. Chem. Soc. 1995, 117,
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8047-8048. For reactions with aldehydes, see: (e) Lee, H. L.; Aube, J. Tetra-
hedron 2007, 63, 9007–9015.
(5) (a) Pearson, W. H.; Schkeryantz, J. M. Tetrahedron Lett. 1992, 33,
5291–5294. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang,
W. K.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183–10194. (c)
Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081-5089. For mercury-
promoted Schmidt reaction, see: (d) Pearson, W. H.; Hutta, D. A.; Fang, W. K. J.
Org. Chem. 2000, 65, 8326-8332. For intermolecular Schmidt reactions with
carbocations, see: (e) Pearson, W. H.; Fang, W. K. J. Org. Chem. 1995, 60, 4960–
4961.
ꢀ
(6) Reddy, D. S.; Judd, W. R.; Aube, J. Org. Lett. 2003, 5, 3899–3902.
(7) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731–734.
(8) (a) Wasserman, H. H. Nature 2006, 441, 699–700. (b) Clayden, J.;
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the effect of the bond rotation on properties of amide bonds.15
However, the synthesis of bridged amides is complicated by
their tendency to undergo rapid hydrolysis,9c and very few
methods allowing their efficient synthesis exist.12b
SCHEME 3
Following our interest in bridged amides and aware of
Pearson’s and Stoltz’s work (Scheme 2), we recently set out to
obtain a new class of bridged lactams that would be formed by
the intramolecular Schmidt ring expansion reaction proceeding
by a formal azide insertion into the distal C-C bond of an R-
azidoalkyl ketone (Scheme 1, path b). In this paper, we present a
full account9m of the study regarding the development of this
version of the intramolecular Schmidt reaction, which allows for
the direct and efficient formation of one-carbon bridged amides
featuring a [4.3.1] bicyclic skeleton. In our approach, the vital
regiochemistry-controlling element is a nonbonded electro-
static interaction between an electron-rich aromatic ring and
the positively charged diazonium cation in the azidohydrin
intermediate. This stabilizing interaction diverts the course
of the Schmidt reaction into the migration of the C-C bond
distal to the reactive ketone. The mechanism, structural
requirements, scope, and coordination effects encountered
during the development of this reaction will be discussed.
SCHEME 4
Results and Discussion
The first example of an intramolecular Schmidt reaction to
afford one-carbon bridged bicyclic lactam was encountered
during a total synthesis of stenine (Scheme 3).2e Thus, triene 1a
underwent intramolecular Diels-Alder reaction to provide
the ketone, which further reacted in situ to give a mixture of the
fused lactam 2a and the bridged isomer 3a. We had earlier
proposed that the regiochemistry of the Schmidt reaction
involves the selective migration of the C-C bond antiperipla-
nar to the leaving diazonium cation (Scheme 3, A and B, bold
bonds).4a In this scenario, chairlike cyclohexanones can only
afford bridged products when two conditions are satisfied: (1)
the azidoalkyl chain occupies an axial orientation and (2) a
diazonium cation is placed in the pseudoaxial position (see the
SI for additional details of this published argument). Accord-
ingly, the antiperiplanar migration of the C-Cbondantitothe
equatorial N2þ group in A would afford the fused isomer 2a,
whereas the axially disposed leaving group in B is necessary for
the formation of the bridged isomer 3a.
The formation of the bridged product 3a was unexpected.
Despite the very extensive use of the intramolecular Schmidt
reaction over the last two decades, the only example of the
intramolecular Schmidt reaction with the azidoalkyl chain
placed in the R position to the electrophile affording a
bridged product had occurred during synthetic studies
toward aspidospermidine (Scheme 4).2g However, this rather
specific case involved the reaction of the azidoalkyl chain
with a ketal, providing a bridged orthoaminal product. We
had earlier proposed that in typical Schmidt reactions the
transition state leading to the bridged product is much less
favorable than the alternative transition states affording the
fused lactam, in part due to the steric penalties paid by the
azidoalkyl chain placed in axial orientation and the diazo-
nium cation occupying the pseudoaxial position.
Motivated by the formation of bridged amide 3a, we first
attempted to affect the equilibrium by disfavoring isomer A
through the placement of a bulky group at the R2 position
(Scheme 3). Toward this end, the isopropyl-containing iso-
mer 1b was prepared and subjected to the reaction condi-
tions; however, essentially the same ratio of bridged/fused
adducts was obtained. Conversely, the analogue bearing a
phenyl group at the same position afforded a dramatically
different result. In this case, fused isomer 2c was formed
exclusively in 85% yield, making this reaction the most
efficient example of this domino sequence observed to date
(Scheme 3). Since the phenyl group has a larger A value (2.8)
than the isopropyl group (2.2),16 we wondered if the appar-
ently exclusive intermediacy of A might be explained by an
attractive through-space interaction between the positively
charged diazonium cation and the phenyl substituent.17
(15) (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951–
6957. (b) Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc.
1996, 118, 8658–8668. (c) Werstiuk, N. H.; Brown, R. S.; Wang, Q. Can. J.
Chem. 1996, 74, 524–532. (d) Kirby, A. J.; Komarov, I. V.; Kowski, K.;
Rademacher, P. J. Chem. Soc., Perkin Trans. 2 1999, 1313–1316. (e) Ly, T.;
Krout, M.; Pham, D. K.; Tani, K.; Stoltz, B. M.; Julian, R. R. J. Am. Chem.
Soc. 2007, 129, 1864–1865. See, also reactivity of bridged lactams reported in
refs 9j and 9k.
(16) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: Hoboken, NJ, 1994.
(17) For reviews, see: (a) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997,
97, 1303–1324. (b) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew.
Chem., Int. Ed. 2003, 42, 1210–1250. (c) Yamada, S. Org. Biomol. Chem.
2007, 5, 2903–2912. (d) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem.
2006, 4, 1195–1201.
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SCHEME 5
SCHEME 6
TABLE 1. Optimization of Product Distribution in the Schmidt Reac-
tion with Azide 1da
Electrostatic through-space interactions have been com-
monly invoked in small-molecule/protein-binding interac-
tions.18 However despite the great utility of such effects in
synthesis, their potential as stereocontrolling elements in
selective organic reactions is yet to be fully realized.19 In
earlier work, we proposed such an interaction as a controlling
feature of certain asymmetric Schmidt reactions of symme-
trical ketones with chiral hydroxyalkyl azides (Scheme 5).20
The diastereoselectivity of this reaction was explained by the
stabilization of the reactive intermediate ax by cation-π
interaction between the aromatic group and the diazonium
cation. Moreover, the selectivity could be correlated with the
electron density of the aromatic substituents,21 leading us to
propose that the stabilization of the diazonium cation by
aromatic rings increased along the expected electrostatic
trend: 3,4,5-trimethoxyphenyl >4-methoxyphenyl > phenyl
>4-nitrophenyl (Scheme 5, box).
Accordingly, we hypothesized that in the currently investi-
gated intramolecular Schmidt reaction (Scheme 3), an
appropriately situated aromatic group might be able to
stabilize the isomer B and provide a direct route to bridged
lactams. Since for an effective cation-π interaction the
aromatic ring and the diazonium cation must be placed in
a 1,3-diaxial relationship, we considered tricyclic intermedi-
ates C, D, and E that could in theory provide access to
bridged amides (Scheme 6, Ar = electron-rich aromatic
ring). Having determined that the removal of the cyclo-
hexene ring in the intermediate E would significantly facili-
tate the synthesis of the required keto-azide precursor, we
entry
acid
equiv
t (h)
2d:3db
1
2
3
4
5
MeAlCl2
EtAlCl2
TfOH
1.0
1.1
5.0
5.0
1.1
1.1
1.1
2.2
2.0
2.0
2.0
2.0
48
18
1
1
18
6
28:72c
50:50
63:37
50:50
71:29
60:40
26:74
47:53
71:29
47:53
26:74
37:63
TiCl4
SnCl4
BF3 Et2O
6
3
7d
8e
9 f
10g
11h
12i
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
6
18
24
24
24
24
a0 °C to rt, c = 0.05-0.15 M in CH2Cl2 unless otherwise noted.
bDetermined by 1H NMR. cBased on isolated yields; 2d isolated in 20%,
3d isolated in 51%. d-78 °C to rt. eReflux, 1.1 equiv added after 2 h. fc =
0.0007 M. gc = 0.007 M. hc = 0.05 M. ic = 0.23 M.
designed a potential cation-π stabilized intermediate F.
Here, a tert-butyl group would serve to lock the conforma-
tion of the azidohydrin intermediate, reducing the number of
reactive intermediates.
Indeed, exposure of the 2-phenyl-substituted azidoalkyl
cyclohexanone 1d to Lewis and protic acids afforded the
bridged amide 3d in an excellent yield (Table 1, entry 1).
Modification of the reaction conditions revealed that a
number of Lewis and protic acids led to the desired bridged
lactam (entries 1-6). Changes in temperature did not im-
prove the bridged/fused ratio (entries 7 and 8). Interestingly,
the product distribution proved to be dependent on the
concentration of the reaction, with ideal results obtained
at c = 0.05 M (entries 9-12).
We propose that Lewis acid treatment of 1d afforded an
equilibrium mixture of G and H (Scheme 7). In this scenario,
the cation-π stabilized intermediate H rearranges to furnish
the bridged amide 3d. Formation of the fused analogue 2d is
explained by the rearrangement of the azidohydrin inter-
mediate G placing the diazonium cation in the pseudoequa-
torial orientation. This intermediate could be formed by
nitrogen inversion or by reversion to keto azide. Although
the cation-π interaction with a phenyl substituent can divert
the reaction pathway into the predominant migration of the
distal C-C bond, the pathway leading to the fused analogue
cannot be completely blocked.
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Ramamurthy, V. Chem. Commun. 2003, 116–117. (c) Kawabata, T.; Nagato,
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Yamada, S. J.; Uematsu, N.; Yamashita, K. J. Am. Chem. Soc. 2007, 129,
12100–12101. (h) Yamada, S.; Inoue, M. Org. Lett. 2007, 9, 1477–1480. (i)
Ishihara, K.; Fushimi, N.; Akakura, M. Acc. Chem. Res. 2007, 40, 1049–
1055. (j) Monje, P.; Paleo, M. R.; Garcia-Rio, L.; Sardina, F. J. J. Org. Chem.
2008, 73, 7394–7397. (k) Richter, I.; Minari, J.; Axe, P.; Lowe, J. P.; James, T.
D.; Sakurai, K.; Bull, S. D.; Fossey, J. S. Chem. Commun. 2008, 1082–1084.
(20) Katz, C. E.; Ribelin, T.; Withrow, D.; Basseri, Y.; Manukyan, A. K.;
Bermudez, A.; Nuera, C. G.; Day, V. W.; Powell, D. R.; Poutsma, J. L.;
ꢀ
Aube, J. J. Org. Chem. 2008, 73, 3318–3327.
(21) (a) Mecozzi, S.; West, A. P.; Dougherty, D. A. J. Am. Chem. Soc.
1996, 118, 2307–2308. (b) Mecozzi, S.; West, A. P.; Dougherty, D. A. Proc.
Natl. Acad. Sci. U.S.A. 1996, 93, 10566–10571.
Control experiments probing the structures of keto-alkyl-
azides required for the synthesis of bridged amides utilizing
1238 J. Org. Chem. Vol. 75, No. 4, 2010

Szostak et al.
JOCArticle
SCHEME 7
The product distribution in the Schmidt reaction of azide
1f appeared to be very dependent on the conditions applied
to promote the rearrangement (Table 2, entries 3 and 4).
These results indicated that the regiochemistry of the
Schmidt reaction is promoter-dependent and suggest that it
may be possible to control reaction regiochemistry by the
appropriate choice of reaction conditions.
SCHEME 8
TABLE 2. Structural Requirements for the Cation-π Directed Schmidt
Reaction
yield (%)
entry
azide
R1
R2
n
acid
2
3
1
2
3
4
5
1e
1e
1f
1f
1g
Ph
Ph
H
H
Ph
H
H
t-Bu
t-Bu
t-Bu
1
1
1
1
2
MeAlCl2
TfOH
MeAlCl2
TiCl4
MeAlCl2
96
85
57
91
17
The effect of reaction conditions on the product distri-
bution in the Schmidt reaction of the non-phenyl group-
containing azide 1f is summarized in Table 3. The results
show that the choice of bond migration in this system, in
which the reactive intermediates (Scheme 8, J and K, R = H)
differ only by the orientation of the diazonium cation,
depend on the choice of Lewis acid promoter. In general,
aluminum containing acids afforded the highest ratio of the
bridged to the fused amide (entries 1-5). The migration of
the C-C bond proximal to the azidoalkyl chain was favored
by the use of sterically demanding Lewis acids (entries
10-13). The product distribution was also influenced by
changes in the reaction temperature (entries 14 and 15).
However, the highest ratio of the bridged to the fused amide
that could be obtained in this system (bridged/fused = 29:71)
was much lower than that in the reaction of the azide 1d
(bridged/fused = 74:26), underscoring the importance of
the cation-π interaction in enhancing the migration of the
distal C-C bond.
Next, we probed the electronic nature of the aromatic
substituent in the R position to the ketone on the outcome of
the Schmidt reaction (Table 4). In these experiments the
bridged amide 3 arises from the cation-π stabilized inter-
mediate, bearing the diazonium cation in a pseudoaxial
orientation (Scheme 7, type H intermediate), whereas the
fused lactam 2 arises from a competing pathway involving
the pseudoequatorial diazonium cation (Scheme 7, type G
cation-π interactions are shown in Table 2. Results ob-
tained with azides 1e and 1f indicate that neither placement
of the phenyl group at the R carbon (Table 2, entries 1 and 2)
nor the axial orientation of the side chain (entries 3 and 4)
alone is sufficient to steer the reaction toward bridged lac-
tam product. However, the combination of an axial azide-
containing tether and an aromatic group in a 1,3-diaxial
relationship with the leaving diazonium cation in the inter-
mediate azidohydrin diverts the reaction so that the bridged
product predominates (3d, Table 1). In addition, a ketone in
which the azide-containing side chain was lengthened to four
carbons did not lead to any productive reaction (Table 2,
entry 5). Such compounds are known to be recalcitrant
substrates for the intramolecular Schmidt reaction.4a
The relevant intermediates are shown in Scheme 8. The fact
that the 1e affords only fused product 2e rules out any effect
arising from differences in intrinsic migratory aptitudes. In this
case the thermodynamically favored conformation of 1e affords
a reactive intermediate I that can lead to only 2e. Interestingly,
the alternative conformation bearing an axial side chain that
could in principle afford the bridged isomer does not appear to
react in this example. However, it very likely exists in the ground
state, suggesting the possibility that conformation I is simply
more reactive than the alternative. The comparison of hydrogen
and phenyl group placement in the conformationally locked
systems is depicted in the bottom part of Scheme 8.
J. Org. Chem. Vol. 75, No. 4, 2010 1239

Szostak et al.
JOCArticle
TABLE 3. Effect of Reaction Conditions on Product Distribution in the
Schmidt Reactions of Azide 1fa
TABLE 5. Influence of Stoichiometry of Lewis Acid on Product
Distributiona,b
entry equiv
acid
2d:3d 2h:3h 2j:3j 2k:3k 2m:3m
1
2
3
4
5
1.0
1.5
2.0
3.0
2.0
MeAlCl2
MeAlCl2
MeAlCl2
MeAlCl2
26:74 12:88 16:84 15:85
26:74 12:88 21:79 22:78
28:72 14:86 30:70 39:61
30:70 29:71 46:54 52:48
24:76
31:69
42:58
61:39
65:35
BF3 CH3CN 56:44 32:68 42:58
3
nd
a0 °C to rt, 24 h, c = 0.05 M in CH2Cl2. bProduct ratio determined by
1H NMR. nd = not determined.
entry
acid
equiv
t (h)
2f:3fb
of the axial/equatorial preference of the diazonium cation
and the strength of the cation-π interaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
15e
MeAlCl2
MeAlCl2
EtAlCl2
AlCl3
1.1
25
2
3
8
1
24
2
2
1
2
2
1
1
1
24
1
71:29
71:29
71:29
77:23
75:25
77:23
78:22
79:21
86:14
85:15
>95:5
90:10
87:13
92:8
Interestingly, the introduction of a 3,4,5-trimethoxy-
phenyl substituent in the R position of the 2-azidoalkyl
cyclohexanone afforded the bridged amide in 66% yield
and the fused analogue in 19% yield (Table 4, entry 4). The
obtained yields correspond to a ratio intermediate between
that of azido-ketones 1d (phenyl-substituted) and 1h (4-
methoxyphenyl-substituted), and do not follow the trend
previously observed in the Schmidt reaction with hydroxy-
alkyl azides (Scheme 5, box).20 Furthermore, the use of 3,4-
dimethoxyphenyl substrate 1k provided a lactam ratio simi-
lar to that obtained from substrate 1j (Table 4, entry 5), while
the 3,4-dioxomethylenephenyl-containing azide 1l (entry 6)
increased the selectivity, matching the ratio obtained with
azide 1h (entry 2). In addition, 3,5-dimethoxyphenyl-con-
taining azide 1m (entry 7) led to a similar ratio of bridged/
fused lactams to that obtained from the phenyl keto-azide in
entry 1. We reasoned that this unanticipated trend in product
distribution could result from coordination of the Lewis acid
to oxygen groups situated on the aromatic ring. To probe this
hypothesis we carried out a set of experiments in which
selected azido-ketones were subjected to a varying number
of equivalents of MeAlCl2. These results are summarized
in Table 5.
1.1
1.1
1.1
1.1
1.1
5.0
Me2AlCl
TMSOTf
BF3 Et2O
3
TfOH
TFA
SnCl4
85c
1.1
5.0
1.1
1.1
1.1
1.1
TiCl4
TiBr4
SbCl5
MeAlCl2
MeAlCl2
79:21
a0 °C to rt, c = 0.05-0.15 M in CH2Cl2. bDetermined by 1H NMR.
cNeat TFA. d-78 °C for 6 h to rt. e90 °C (MW).
TABLE 4. Synthesis of Fused and Bridged Lactamsa
In the case of the azide 1d the ratio bridged/fused amide
remains practically constant, regardless of the stoichiometry
of MeAlCl2 (Table 5, entries 1-4, 2d:3d). However, with
alkoxy-substituted phenyl rings, the bridged/fused lactam
ratio decreases with the increase of equivalents of the Lewis
acid used. This trend is more pronounced in substrates
capable of coordination of MeAlCl2 to multiple oxygens
(Table 5, entries 1-4, series j, k, m). Furthermore, using a
monodentate acid to promote the rearrangement affords a
similar trend of bridged/fused lactams regardless of aromatic
oxygenation pattern (4-methoxyphenyl > 3,4,5-trimethoxy-
phenyl > phenyl > 3,5-dimethoxyphenyl) (Table 5, entry 5).
These results are consistent with coordination of the acid
to oxygens on the aromatic ring, resulting in the decrease of
the electron density of π-systems and the concomitant
weakening of cation-π interactions. The net outcome is an
increased amount of the þfused lactam formed from the
intermediate bearing a N2 group in the pseudoequatorial
orientation (Scheme 7, type G intermediate). In addition, a
steric interaction between the acid coordinated to oxygens on
the aromatic ring and diazonium cation in the pseudoaxial
orientation might also be responsible for a lower selectivity in
the C-C bond migration. It is also possible that the diazo-
nium cation in the pseudoaxial orientation is disfavored by
electronic dipoles formed upon coordination of the acid to
oxygenated substrates. Finally, it is not possible to comple-
tely discard a role of changing the migratory aptitude with
yield (%)
entry
azide
Ar
2
3
1
2
3
4
5
6
7
1d
1h
1i
1j
1k
1l
C6H5
4-(MeO)C6H4
4-(NO2)C6H4
3,4,5-(MeO)3C6H2
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
3,5-(MeO)2C6H3
22
11
38
19
18
13
25
61
71
39
66
65
72
65
1m
a1.5 equiv of MeAlCl2, 0 °C to rt, 24 h, 0.05 M in CH2Cl2.
intermediate). The observed overall dependence of selecti-
vity is consistent with the ability of aryl rings to stabilize the
N2 group in a 1,3-diaxial relationship. Thus, under opti-
þ
mized conditions, the azide 1d bearing a phenyl in the R
position afforded 61% of the bridged lactam 3d along with
22% of the fused product 2d (Table 4, entry 1). The azide 1h,
featuring a more electron-rich 4-methoxyphenyl system, led
to the increased bridged/fused lactam ratio, delivering
the amides in 71% and 11% yields, respectively (Table 4,
entry 2). Conversely, the azide 1i decorated with an elec-
tron-withdrawing 4-nitrophenyl substituent decreased the
ratio, affording ca. 1:1 distribution of the final products
(Table 4, entry 3). This trend is fully consistent with the
expectation that the observed selectivities are a direct result
1240 J. Org. Chem. Vol. 75, No. 4, 2010

Szostak et al.
JOCArticle
SCHEME 9
TABLE 6. Schmidt Reactions of R-Carbonyl Substituted Azides
possibly forming a six-membered chelate, which might rea-
sonably be expected to disfavor the orientation of the
diazonium cation in the pseudoaxial position (Scheme 9,
intermediate L).
Summary
The intramolecular Schmidt reaction of 2-azidoalkyl
ketones can be utilized to efficiently prepare medium-
bridged twisted amides having a [4.3.1] bicyclic scaffold.
Despite the large potential utility of such compounds, they
are very difficult to synthesize with use of other currently
available methods. Our work shows that electrostatic
cation-π interactions can be applied as the key regiochemi-
stry-controlling element, allowing the migration of the typi-
cally disfavored C-C bond distal to the reactive R-ketone.
This contrasts with the results of Pearson and Stoltz, in
which formation of a bridged intermediate occurred but did
not suffer the onus of forming a bridged cation or was
mandated by the nonadjacent disposition of the ketone
and the azide-containing side chain (Scheme 2). In R-aryl-
substituted 2-azidoalkyl ketones, cation-π effects are con-
sistent with the dependence of selectivity on the electronic
density of R-substituted aryl groups; however, coordination
influence cannot be neglected in this system.
Overall, this methodology significantly extends the utility
of the intramolecular Schmidt reaction in the synthesis of
nontraditional lactams. Furthermore, it demonstrates that
cation-π interactions are a very effective conformation-
controlling tool, and can be utilized to favor the formation
of unstable ring systems. Future work will address the
application of cation-π effects to the synthesis of other
bridged structures and focus on the use of electrostatic
interactions as a stereochemistry-controlling tool. One-carbon
bridged amides prepared in this study are currently utilized to
investigate the influence of the amide bond distortion on the
properties of these compounds.
yield (%)
entry
azide
R
acid
2
3
1
2
3
4
5
6
1n
1n
1n
1n
1o
1o
CO2Et
CO2Et
CO2Et
CO2Et
CONHBu
CONHBu
MeAlCl2
TfOH
TFA
80
92
88
78
52
77
BF3 Et2O
TfOH
MeAlCl2
3
13
the modification of the reaction parameters. Overall, these
results emphasize the importance of selecting appropriate
reaction conditions to obtain maximum cation-π stabiliza-
tion effects.
Motivated by Yamada et al. finding that carbonyl groups
can serve as effective π-systems,22 we examined the potential
of ester and amide functionalities as cation-stabilizing
groups in the intramolecular Schmidt reaction (Table 6).
However, the presence of an ethoxycarbonyl group in a
conformationally locked system afforded only the fused
amide in good yields (entries 1-4). The placement of the
secondary amide in the R position to the ketone allowed for
the formation of the bridged amide 3o (entry 5). However,
the ratio of bridged/fused lactams resembled the outcome
obtained with azide 1f (Table 2, entry 3) rather than cases in
which we propose cation-π interactions to be operative.
Interestingly, when the reaction of the azide 1o was pro-
moted by a Lewis acid instead of a protic acid, the formation
of the bridged amide was not observed (entry 6). This
suggests that the Lewis acid coordinates to the amide group,
Experimental Section
General Procedure for Schmidt Reactions in the Tricyclic
Series. To a solution of azidoketone 1 (1.0 equiv) in CH2Cl2
(22) Yamada, S.; Misono, T.; Tsuzuki, S. J. Am. Chem. Soc. 2004, 126,
9862–9872.
J. Org. Chem. Vol. 75, No. 4, 2010 1241

Szostak et al.
JOCArticle
1
was added MeAlCl2 (1.0 equiv) dropwise at 0 °C, then the
reaction was allowed to reflux for 20 h. The reaction was cooled
to 0 °C, partitioned between saturated NaHCO3 and EtOAc,
and the organic layer was dried with Na2SO4, filtered, and
concentrated. Flash chromatography afforded the title lactams.
Note: Typically, bridged lactams 3 are less polar and more UV
active than fused lactams 2. This is yet another consequence of
the decreased conjugation of the lone pair of electrons at
nitrogen with the amide CdO system.
Lactams 2b and 3b. The reaction of azidotriene 1b (0.87 g,
3.3 mmol, 1.0 equiv) and MeAlCl2 (1.0 M in hexanes, 3.3 mL,
3.3 mmol) in CH2Cl2 afforded after chromatography 2b (0.33 g,
43%) as an oil and 3b (0.22 g, 28%) as an oil.
Compound 3d: H NMR (400 MHz, CDCl3) δ 0.99 (s, 9H),
1.53-1.55 (m, 1H), 1.64 (t, J = 11.6 Hz, 1H), 1.84-2.12
(complex, 6H), 2.53-2.56 (m, 1H), 2.60-2.68 (m, 1H),
3.33-3.41 (m, 1H), 3.71-3.74 (m, 1H), 3.92-3.97 (m, 1H),
7.17-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 22.4, 26.1,
28.0, 34.1, 37.6, 43.1, 44.1, 50.2, 54.8, 56.2, 126.1, 126.2, 128.5,
147.6, 184.4; IR (neat) 1685 cm-1; HRMS calcd for C19H28NO
(Mþ þ H) 286.2165, found 286.2173.
(8S,9aR)-8-tert-Butyl-9a-(4-methoxyphenyl)hexahydro-1H-
pyrrolo[1,2-a]azepin-5(6H)-one (2h) and (4R,6R)-4-tert-Butyl-
6-(4-methoxyphenyl)-1-azabicyclo[4.3.1]decan-10-one (3h). The
reaction of azide 1h (0.0841 g, 0.25 mmol, 1.0 equiv) and
MeAlCl2 (1.0 M in hexanes, 0.37 mL, 1.5 equiv) in CH2Cl2
(4.5 mL, 0.05 M) for 24 h afforded after chromatography (1/2
hexanes/EtOAc-EtOAc) lactam 2h (0.0090 g, 0.028 mmol,
yield 11%) as an oil and lactam 3h (0.0556 g, 0.0177 mmol,
yield 71%) as a white solid (mp 135-136 °C).
Compound 2b: 1H NMR (400 MHz, CDCl3) δ 0.86-0.93 (m,
6H), 1.32-1.44 (m, 2H), 1.50-1.55 (m, 1H), 1.61-1.84
(complex, 4H), 1.95-2.01 (m, 2H), 2.13-2.19 (m, 2H),
3.22-3.27 (m, 1H), 3.40-3.45 (m, 1H), 3.56-3.64 (m, 1H),
5.45-5.49 (m, 1H), 5.62-5.65 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.7, 22.5, 24.3, 26.1, 27.6, 29.1, 29.5, 37.6, 38.5, 46.6,
54.6, 62.2, 125.8, 130.8, 173.2; IR (neat) 1623 cm-1; HRMS
calcd for C15H24NO (Mþ þ H) 234.1858, found 234.1855.
Compound 3b: 1H NMR (400 MHz, CDCl3) δ 0.86-0.93 (m,
6H), 1.50-1.62 (m, 2H), 1.61-1.84 (complex, 8H), 2.30-2.51
(complex, 3H), 3.02-3.10 (m, 1H), 3.71-3.75 (m, 1H),
5.64-5.67 (complex, 2H); 13C NMR (100 MHz, CDCl3) δ
19.9, 20.4, 27.8, 28.5, 30.5, 32.4, 33.2, 36.1, 41.4, 56.2, 57.4,
73.7, 128.4, 132.4, 187.6; IR (neat) 1695 cm-1; HRMS calcd for
C15H24NO (Mþ þ H) 234.1858, found 234.1878.
1
Compound 2h: H NMR (400 MHz, CDCl3) δ 0.91 (s, 9H),
1.31-1.55 (complex, 4H), 1.71-1.73 (m, 1H), 1.90-1.92 (m,
1H), 2.06-2.18 (complex, 3H), 2.27-2.32 (m, 1H), 2.46-2.50
(m, 1H), 3.42-3.71 (m, 2H), 3.82 (s, 3H), 6.87-6.91 (m, 2H),
7.15-7.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.6, 24.7,
27.1, 32.6, 33.0, 39.5, 41.4, 43.0, 47.5, 55.3, 68.1, 113.8, 125.9,
139.2, 158.4, 172.3; IR (neat) 1625 cm-1; HRMS calcd for
C20H30NO2 (Mþ þ H) 316.2277, found 316.2278.
1
Compound 3h: H NMR (400 MHz, CDCl3) δ 0.98 (s, 9H),
1.51-1.54 (m, 1H), 1.61 (t, J = 11.5 Hz, 1H), 1.83-2.08
(complex, 6H), 2.48-2.51 (m, 1H), 2.61-2.67 (m, 1H),
3.32-3.37 (m, 1H), 3.69-3.72 (m, 1H), 3.81 (s, 3H),
3.91-3.95 (m, 1H), 6.88-6.90 (m, 1H), 7.27-7.29 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 22.5, 26.1, 28.0, 34.1, 37.6, 43.1,
44.4, 50.2, 54.8, 55.3, 55.6, 113.8, 127.1, 140.0, 157.8, 184.6; IR
(neat) 1685 cm-1; HRMS calcd for C20H30NO2 (Mþ þ H)
316.2277, found 316.2278.
(3R,7aS,10aR,11S)-1,2,3,6,7,7a,8,10a-Octahydro-3-phenyl-
azepino[3,2,1-hi]indol-4(11H)-one (2c). The reaction of azido-
triene 1c (2.9 g, 10 mmol, 1.0 equiv) and MeAlCl2 (1.0 M in
hexanes, 10 mL, 10 mmol) in CH2Cl2 afforded after chroma-
tography 2c (2.3 g, 85%) as a white solid (mp 132-134 °C).
Bridged lactam 3b was not detected by TLC and NMR analysis
1
(8S,9aR)-8-tert-Butyl-9a-(4-nitrophenyl)hexahydro-1H-pyr-
rolo[1,2-a]azepin-5(6H)-one (2i) and (4R,6R)-4-tert-Butyl-6-(4-
nitrophenyl)-1-azabicyclo[4.3.1]decan-10-one (3i). The reaction
of azide 1i (0.0872 g, 0.24 mmol, 1.0 equiv) and MeAlCl2 (1.0 M
in hexanes, 0.37 mL, 1.5 equiv) in CH2Cl2 (4.4 mL, 0.05 M) for
24 h afforded after chromatography (1/2 hexanes/EtOAc-
EtOAc) lactam 2i (0.0301 g, 0.091 mmol, yield 38%) as a white
solid (mp 177-178 °C, Rf 0.53, 1/1 EtOAc/hexanes) and lactam
3i (0.0312 g, 0.095 mmol, yield 39%, Rf 0.84, 1/1 EtOAc/
hexanes) as a white solid (mp 135-136 °C).
of the crude reaction mixture. H NMR (400 MHz, CDCl3) δ
1.49-1.75 (complex, 5H), 2.10-2.19 (m, 2H), 2.20-2.36 (m,
2H), 2.50-2.56 (m, 1H), 2.88-2.94 (m, 1H), 3.69-3.75 (m, 2H),
4.10-4.16 (m, 1H), 5.32-5.36 (m, 1H), 5.56-5.59 (m, 1H),
7.19-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 25.4, 26.9,
28.1, 30.0, 35.5, 38.4, 46.8, 50.4, 62.8, 125.9, 126.4, 126.5, 129.2,
131.0, 140.5, 171.9; IR (neat) 1623 cm-1; HRMS calcd for
C18H22NO (Mþ þ H) 268.1709, found 268.1701.
General Procedure for the Cation-π Directed Schmidt Reac-
tion in the Bicyclic Series. To a solution of azidoketone 1 (1.0
equiv) in CH2Cl2 (0.05 M) was added MeAlCl2 (1.5 equiv)
dropwise at 0 °C, then the reaction was allowed to slowly warm
to rt and stirred for 24 h. The reaction was cooled to 0 °C,
quenched with water (10 mL), and extracted with CH2Cl2 (3 ꢀ
20 mL). The organic layer was washed with brine (1 ꢀ 20 mL),
dried (Na2SO4), and concentrated. Flash chromatography
afforded the title lactams.
1
Compound 2i: H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H),
1.24-1.43 (m, 3H), 1.49-1.56 (m, 1H), 1.74-1.81 (m, 1H),
1.88-1.95 (m, 1H), 2.07 (dt, J = 6.0, 12.8 Hz, 1H), 2.12-2.26
(m, 2H), 2.34 (dd, J = 4.3, 12.6 Hz, 1H), 2.53 (d, J = 13.9 Hz, 1H),
3.64-3.77 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.9 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 19.7, 24.5, 27.0, 32.7, 33.0,
39.0, 41.4, 43.2, 47.6, 68.5, 123.9, 126.0, 147.0, 154.7, 172.2; IR (neat)
2961, 2870, 1636, 1597, 1518, 1452, 1421, 1348, 731 cm-1; HRMS
calcd for C19H27N2O3 (Mþ þ H) 331.2022, found 331.2008.
(8S,9aR)-8-tert-Butyl-9a-phenylhexahydro-1H-pyrrolo[1,2-a]-
azepin-5(6H)-one (2d) and (4R,6R)-4-tert-Butyl-6-phenyl-1-aza-
bicyclo[4.3.1]decan-10-one (3d). The reaction of azide 1d (0.0904
g, 0.29 mmol, 1.0 equiv) and MeAlCl2 (1.0 M in hexanes, 0.43
mL, 1.5 equiv) in CH2Cl2 (5.4 mL, 0.05 M) for 24 h afforded
after chromatography (1/3 hexanes/EtOAc-EtOAc) lactam 2d
(0.0185 g, 0.065 mmol, yield 22%) as an oil (Rf 0.40, 1/1 EtOAc/
hexanes) and lactam 3d (0.0502 g, 0.0176 mmol, yield 61%) as an
oil (Rf 0.70, 1/1 EtOAc/hexanes).
1
Compound 3i: H NMR (400 MHz, CDCl3) δ 0.99 (s, 9H),
1.53-1.72 (m, 2H), 1.81-2.04 (m, 6H), 2.56 (d, J = 11.7 Hz,
1H), 2.62-2.72 (m, 1H), 3.40 (m, 1H), 3.74 (d, J = 10.2 Hz, 1H),
3.93 (dd, J = 5.9, 13.4 Hz, 1H), 7.52 (d, J = 6.8 Hz, 2H), 8.21 (d,
J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 22.3, 25.9, 28.0,
34.1, 37.0, 43.0, 44.2, 50.1, 54.6, 56.3, 123.8, 127.3, 146.3, 154.8,
183.1; IR (neat) 2957, 2876, 1666, 1603, 1518, 1348, 1317, 1186,
1177, 732 cm-1; HRMS calcd for C19H27N2O3 (Mþ þ H)
331.2022, found 331.2044.
(8S,9aR)-8-tert-Butyl-9a-(3,4,5-trimethoxyphenyl)hexahydro-
1H-pyrrolo[1,2-a]azepin-5(6H)-one (2j) and (4R,6R)-4-tert-Bu-
tyl-6-(3,4,5-trimethoxyphenyl)-1-azabicyclo[4.3.1]decan-10-one (3j).
The reaction of azide 1j (0.0779 g, 0.19 mmol, 1.0 equiv) and
MeAlCl2 (1.0 M in hexanes, 0.29 mL, 1.5 equiv) in CH2Cl2 (3.6 mL,
0.05 M) for 24 h afforded after chromatography (1/1 hexanes/
1
Compound 2d: H NMR (400 MHz, CDCl3) δ 0.92 (s, 9H),
1.31-1.42 (complex, 3H), 1.52-1.58 (m, 1H), 1.71-1.73 (m,
1H), 1.90-1.92 (m, 1H), 2.11-2.18 (complex, 3H), 2.28-2.32
(m, 1H), 2.50-2.54 (m, 1H), 3.60-3.73 (m, 2H), 7.13-7.37 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 19.7, 24.6, 27.1, 32.6, 33.0,
39.3, 41.4, 43.0, 47.5, 68.6, 124.8, 126.8, 128.5, 147.1, 172.4; IR
(neat) 1635 cm-1; HRMS calcd for C19H28NO (Mþ þ H)
286.2165, found 286.2173.
1242 J. Org. Chem. Vol. 75, No. 4, 2010

Szostak et al.
JOCArticle
EtOAc-EtOAc) lactam 2j (0.0136 g, 0.036 mmol, yield 19%) as an
oil (Rf 0.28, 1/1 EtOAc/hexanes) and lactam 3j (0.0473 g, 0.126
mmol, yield 66%, Rf 0.53, 1/1 EtOAc/hexanes) as a solid (mp
158-159 °C).
(m, 1H), 3.70 (d, J = 11.0 Hz, 1H), 3.83 (d, J = 4.0 Hz, 3H), 3.87
(d, J = 3.8 Hz, 6H), 3.90-3.97 (m, 1H), 6.55 (d, J = 3.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 22.5, 25.9, 28.0, 34.1, 37.6, 43.1,
44.3, 50.3, 54.6, 56.2, 56.4, 60.8, 103.7, 136.6, 143.4, 153.1, 184.2;
IR (neat) 2950, 1660, 1580, 1405, 1325, 1245, 1120 cm-1; HRMS
calcd for C22H34NO4 (Mþ þ H) 376.2488, found 376.2482.
1
Compound 2i: H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H),
1.22-1.52 (m, 3H), 1.58 (t, J = 13.2 Hz, 1H), 1.66-1.78 (m,
1H), 1.86-1.97 (m, 1H), 2.05-2.19 (m, 2H), 2.21-2.36 (m, 2H),
2.42 (d, J = 14.0 Hz, 1H), 3.58-3.74 (m, 2H), 3.86 (s, 9H), 6.37
(d, J = 3.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 19.8, 24.7,
27.1, 32.7, 32.9, 39.2, 41.6, 43.0, 47.6, 56.3, 60.8, 68.8, 102.2,
136.9, 143.0, 153.2, 172.4; IR (neat) 2960, 1630, 1580, 1500,
1445, 1405, 1325, 1235, 1120 cm-1; HRMS calcd for C22H34NO4
(Mþ þ H) 376.2488, found 376.2477.
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM-49093) for financial support
and Victor Day for X-ray crystallography.
Supporting Information Available: Experimental details
and characterization data for new compounds. This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
1
Compound 3j: H NMR (400 MHz, CDCl3) δ 0.98 (s, 9H),
1.50 (m, 1H), 1.54-1.63 (m, 1H), 1.85-1.97 (m, 5H), 2.07 (m,
1H), 2.49 (d, J = 11.9 Hz, 1H), 2.59-2.67 (m, 1H), 3.30-3.38
J. Org. Chem. Vol. 75, No. 4, 2010 1243