Proximity effects in nucleophilic addition reactions to medium-bridged twisted lactams: Remarkably stable tetrahedral intermediates

Article abstract of DOI:10.1021/ja909792h

The reactions of a series of strained bicyclic and tricyclic one-carbon bridged lactams with organometallic reagents have been investigated. These amides permit isolation of a number of remarkably stable hemiaminals upon nucleophilic addition to the twisted amide bonds present in the lactam precursors. The factors that affect the stability of the resulting bridged hemiaminals are presented. In some cases, the hemiaminals were found to collapse to the open-form amino ketones in a manner expected for traditional carboxylic acid derivatives. Transannular N · · · C=O interactions were also observed in some nine-membered amino ketones. Additionally, tricyclic bridged lactams were found to react with some nucleophiles that typically react with ketones but not with planar amides. The effect of geometry on the reactivity of amide bonds and the amide bond distortion range that marks the boundary of amide-like and ketone-like carbonyl reactivity of lactams are also discussed.

Full text of DOI:10.1021/ja909792h

Published on Web 01/22/2010
Proximity Effects in Nucleophilic Addition Reactions to
Medium-Bridged Twisted Lactams: Remarkably Stable
Tetrahedral Intermediates
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
Received November 18, 2009; E-mail: jaube@ku.edu
Abstract: The reactions of a series of strained bicyclic and tricyclic one-carbon bridged lactams with
organometallic reagents have been investigated. These amides permit isolation of a number of remarkably
stable hemiaminals upon nucleophilic addition to the twisted amide bonds present in the lactam precursors.
The factors that affect the stability of the resulting bridged hemiaminals are presented. In some cases, the
hemiaminals were found to collapse to the open-form amino ketones in a manner expected for traditional
carboxylic acid derivatives. Transannular N · · ·CdO interactions were also observed in some nine-membered
amino ketones. Additionally, tricyclic bridged lactams were found to react with some nucleophiles that typically
react with ketones but not with planar amides. The effect of geometry on the reactivity of amide bonds and
the amide bond distortion range that marks the boundary of amide-like and ketone-like carbonyl reactivity
of lactams are also discussed.
Introduction
The tetrahedral intermediate formed in the addition of
nucleophiles to carboxylic acid derivatives is typically a short-
lived species that is sometimes detected but rarely isolated.1
Thus, although tetrahedral intermediates formed in the reaction
of tertiary amides2 and N-methoxy-N-methylamides3 with
organometallic reagents are relatively stable as their salts, and
have been used extensively for synthesis of ketones, the
tetrahedral intermediates themselves rapidly decompose upon
protonation (Figure 1a). In addition, isolated tetrahedral inter-
mediates would provide models for in vivo transacylation
processes. Thus, the products of thiol-, alcohol-, and amine-
based nucleophiles with esters or amides are commonly
encountered in enzymatic acylation reactions, but are difficult
to investigate in the absence of enzyme stabilization.4
Figure 1. (a) Reaction of carboxylic acid derivatives with nucleophiles;
and (b) examples of N· · ·CdO interactions.
groups in close proximity to limit the number of unproductive
conformations. It is generally accepted that the Bu¨rgi-Dunitz
angle, so determined, is followed by nucleophiles in their attack
on carboxylic acid derivatives, producing tetrahedral intermedi-
ates.7 Herein, we report that medium-bridged twisted amides8
can serve as model systems to monitor a transition from stable
tetrahedral intermediates through intramolecular N · · ·CdO
interactions to unstable tetrahedral intermediates. As a result
of this investigation, we also provide evidence that a rotation
of an amide bond to ca. 50° (where 0° would correspond to
Transannular N · · ·CdO interactions between tertiary amines
and carbonyl groups5 were primary tools in a fundamental study
by Bu¨rgi and Dunitz6 to designate the trajectory of the attack
of nucleophiles on CdO bonds (Figure 1b). In this investigation,
a set of conformationally frozen amino-ketones kept the reactive
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Chem. 2005, 18, 193–209. (b) Deslongchamps, P. Stereoelectronic
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For examples of isolated tetrahedral intermediates, see: (c) Evans,
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3188–3191. (d) Kirby, A. J.; Komarov, I. V.; Feeder, N. J. Am. Chem.
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2078 J. AM. CHEM. SOC. 2010, 132, 2078–2084
10.1021/ja909792h  2010 American Chemical Society

Proximity Effects in Nucleophilic Addition Reactions
A R T I C L E S
planar amide and 90° to fully orthogonal amide bond)9 is close
to the border from an amide-like to ketone-like switch of
reactivity of amide carbonyl groups.
Table 1. Hydride Addition to Bridged Amides
Recently, our laboratory described that one-carbon bridged
amides undergo novel C-N bond cleavage reactions, which
are a direct result of the distortion of amide linkage.10 We
also found that despite significant twist values of the amide
bonds, one-carbon bridged lactams are much less readily
hydrolyzed by nucleophilic solvents when compared to fully
twisted lactams.11 This unusual-to-twisted-amides property
was ascribed to destabilization of the potentially formed
carboxylic acid and amine functionalities by their placement
on the opposite sides of the medium-sized ring, where they
were additionally subjected to strong proximity effects. We
hypothesized that such lactams might undergo facile nucleo-
philic addition reactions and additionally permit the isolation
of stable tetrahedral intermediates. This supposition was
supported by the very limited but important precedent
obtained by Kirby8h and Coe8i groups in the study of highly
constrained adamantane-like twisted amides, in which lactam
transformations afforded stabilized hemiaminals.12
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429. (b) Rademacher, P. Chem. Soc. ReV. 1995, 24, 143–150. For
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(6) (a) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,
95, 5065–5067. (b) Bu¨rgi, H. B.; Dunitz, J. D.; Lehn, M. J.; Wipff,
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Results and Discussion
(7) For an important study with 1-azaadamantane derivative, see: Davies,
J. E.; Kirby, A. J.; Komarov, I. V. HelV. Chim. Acta 2003, 86, 1222–
1233.
Additions to Bicyclic Bridged Amides. We began our study
by investigating the behavior of one-carbon bridged amides in
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549–555. (b) Lease, T. G.; Shea, K. J. AdVances in Theoretically
Interesting Molecules; JAI Press Inc.: Greenwich, CT, 1992; Vol. 2,
pp 79-112. (c) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.
Amide Linkage: Selected Structural Aspects in Chemistry, Biochem-
istry,and Materials Science; Wiley: New York, 2000. (d) Clayden, J.;
Moran, W. J. Angew. Chem., Int. Ed. 2006, 45, 7118–7120. For
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Chem. Soc. 1989, 111, 1073–1081. (g) Lease, T. G.; Shea, K. J. J. Am.
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Feeder, N. J. Chem. Soc., Perkin Trans. 2 2001, 522–529. (i) Bashore,
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see: (a) Forlani, L.; Marianucci, E.; Todesco, P. E. J. Chem. Res., Synop.
1984, 126–127. (b) Chudek, J. A.; Foster, R.; Young, D. J. Chem. Soc.,
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2005, 126, 745–751. (h) Iwasawa, T.; Hooley, R. J.; Rebek, J. Science
2007, 317, 493–496. (i) Kawamichi, T.; Haneda, T.; Kawano, M.; Fujita,
M. Nature 2009, 461, 633–635For examples of hemiaminals stabilized
due to electronic means, see: (j) Chang, Y. A.; Sun, T. H.; Chiang, M. Y.;
Lu, P. J.; Huang, Y. T.; Liang, L. C.; Ong, C. W. Tetrahedron 2007, 63,
8781–8787. (k) Troast, D. M.; Porco, J. A. Org. Lett. 2002, 4, 991–
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9
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A R T I C L E S
Szostak et al.
Scheme 1. Reduction of Bridged Lactams with Cleavage of C-C
Bond
conversion irreversible. Overall, the results from Table 1 and
Scheme 1 demonstrate that the nature of the R-substituent plays
a key role in determining the fate of tetrahedral intermediates
generated from these bicyclic systems.
Using amide 1a as a test substrate, we also briefly investigated
the role of a hydride source and reaction conditions on the
formation and fates of stable hemiaminals (see the Supporting
Information for full details).16 A number of reducing reagents
(including LiBH4, LiAlH4, DIBAl-H, and BH3) afforded
isolable hemiaminal 2a. Interestingly, the reduction rate with
NaBH4 was found to be qualitatively slower in methanol as a
solvent than in ethanol, which contrasts with the reduction of
typical carbonyl groups by NaBH4.17 In addition, the reduction
of 1a was suppressed when CeCl3 was utilized as an additive.18
It is possible that the decreased reaction rates are due to the
increased basicity of the nonplanar amide bond nitrogen, leading
to subsequent hydrogen bonding or metal coordination to the
amide bond nitrogen. We have previously demonstrated that
N-protonation, -alkylation, or -metalation occurred to a much
greater degree in bridged lactams than in normal amides;10
however, it is not clear why in the present case coordination to
the nitrogen did not increase the carbonyl reactivity by inductive
effect. Importantly, when a one-carbon higher homologue of
1a ([5.3.1] ring system) was treated with NaBH4, reduction was
not observed, indicating that the [5.3.1] scaffold is not suf-
ficiently distorted to permit hydride addition under these
conditions.
addition reactions of hydride, the smallest available nucleophile
(Table 1). In agreement with our hypothesis, treatment of
bridged bicyclic amide 1a with NaBH4 (1.0 equiv) in EtOH
led to the formation of stable hemiaminal 2a in excellent yield
(entry 1). Because planar amides are typically not reduced by
NaBH4,13x this transformation occurs due to the increased
reactivity of the bridged amide bond. The stability of 2a may
indicate that the lone pairs of electrons at oxygen do not overlap
with the σ*C-N bond in the bicyclic hemiaminal system.
Furthermore, because the reduction stops at the tetrahedral
intermediate stage, the bridged nitrogen atom is incapable of
donation of its n electrons into the σ*C-O. We recently reported
that a series of epoxy-hemiaminals are similarly stabilized.14
However, aside from Kirby and Coe precedents noted above,
we are unaware of other conversions of nonadamantane twisted
amides to a stable hemiaminal under mild, protic conditions.15
To examine the effect of structure on the stability of
hemiaminals, the reduction was extended to a number of bridged
amides. Bridged lactam substrates were prepared via the
intramolecular Schmidt reaction as previously reported,8l gener-
ally as the minor component of a mixture also containing the
regioisomeric fused lactam; the additional tert-butyl group was
incorporated to enhance the proportion of bridged product
obtained. Thus, bicyclic amides with electron-rich aromatic rings
in the R-position as well as tricyclic lactams smoothly underwent
the reduction, providing isolable hemiaminals in all cases studied
(Table 1, entries 2-6). However, an R-unsubstituted bridged
amide and amides with sulfides in the R position led to a mixture
of hemiaminals and primary alcohols (entries 7-9). This
outcome suggests that, although these structure types display
similarly enhanced reactivity to fully planar lactams and thus
reaction with NaBH4, the products more readily collapse under
the reaction conditions to afford aldehydes that undergo further
in situ reduction.
Because hemiaminals are versatile synthetic intermediates,19
we examined the behavior of these bridged hemiaminals in a
variety of settings (Scheme 2). Noteworthy transformations
included the oxidation of 2a to the parent amide 1a and,
conversely, full reduction to amine 5 (most likely proceeding
via the intermediacy of a rarely encountered bridgehead iminium
ion).20 This latter possibility was also consistent with the
isolation of aminals 6 and 7 as single diastereoisomers from a
(15) For examples of bridged amides that form unstable hemiaminals upon
reduction, see: (a) Denzer, M.; Ott, H. J. Org. Chem. 1969, 34, 183–
187. (b) Levkoeva, E. I.; Nikitskaya, E. S.; Yakhontov, L. N. Dokl.
Akad. Nauk 1970, 192, 342–345. (c) Levkoeva, E. I.; Nikitskaya, E. S.;
Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1971, 378–384. For
preparation of relevant 2-quinuclidinol derivatives, see: (d) Bochow,
H.; Schneider, W. Ber. 1975, 108, 3475–3482. For reduction of a
bridged lactam derived from 8-azabicyclo[3.2.1]octane scaffold, see:
(e) Baylis, A. M.; Davies, M. P. H.; Thomas, E. J. Org. Biomol. Chem.
2007, 5, 3139–3155. For additional examples of reduction of more
relaxed ring systems of bridged lactams to hemiaminals, see: (f) Ban,
Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981, 103,
6990–6992. (g) Arata, Y.; Kobayashi, T. Chem. Pharm. Bull. 1972,
20, 325–329. (h) Bu¨chi, G.; Coffen, D. L.; Kocsis, K.; Sonnet, P. E.;
Ziegler, F. E. J. Am. Chem. Soc. 1965, 87, 2073–2075. For examples
of reduction of more relaxed ring systems of bridged lactams to amines,
see: (i) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47,
4221–4223. (j) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin,
K.; Lannou, M. I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70,
10538–10551. (k) Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.;
McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am.
Chem. Soc. 1993, 115, 8116–8129. (l) Amat, M.; Coll, M. D.; Bosch,
J.; Espinosa, E.; Molins, E. Tetrahedron: Asymmetry 1997, 8, 935–
948. For examples of bridged hemiaminals used in total synthesis
projects but prepared by methods other than reduction of amide bonds,
see: (m) Kutney, J. P.; Balsevich, J.; Bokelman, G. H.; Hibino, T.;
Honda, T.; Itoh, I.; Ratcliffe, A. H.; Worth, B. R. Can. J. Chem. 1978,
56, 62–70. (n) Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.;
Rainey, T. J.; Westlund, N.; Lynch, V. Tetrahedron 2002, 58, 3423–
3443.
Remarkably, reduction of bridged amides decorated with
R-electron-withdrawing substituents afforded formamides (Scheme
1). In these examples, ready hemiaminal formation ultimately
results in the formation of anions, stabilized by sulfonyl and
4-nitrophenyl groups (1j and 1k) or allylic olefin and amide
bond (1l). The hemiaminal intermediate may well be in
equilibrium with the corresponding amino aldehyde intermedi-
ate, but the observed products likely predominate because the
anionic intermediate is readily protonated, rendering the overall
(16) Hudlicky, M. Reductions in Organic Chemistry; American Chemical
Society: Washington, DC, 1996.
(17) Brown, H. C.; Mead, E. J.; Rao, B. C. S. J. Am. Chem. Soc. 1955, 77,
6209–6213.
(13) Brown, H. C.; Rao, B. C. S. J. Am. Chem. Soc. 1955, 77, 3164–3164.
(14) Szostak, M.; Aube´, J. J. Am. Chem. Soc. 2009, 131, 13246–13247.
(18) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
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Proximity Effects in Nucleophilic Addition Reactions
A R T I C L E S
Scheme 2. Synthetic Transformations of Bridged Hemiaminals
Table 2. Organometallic Addition to Bicyclic Amides
entry
amino-ketone
R
reagent
yield [%]
1
2
3
4
5
8a
8a
8b
8c
8d
Me
Me
n-Bu
sec-Bu
tert-Bu
MeLi
MeMgI
n-BuLi
sec-BuLi
tert-BuLi
89
73
83
93
80
Table 3. Organometallic Addition to Tricyclic Amides
entry
amide
hemiaminal/amino-ketone
R2
reagent
yield [%]
mixture of hemiketal isomers in acidic methanol and by the
determination that hemiaminal 2a readily epimerizes upon
treatment with acid. Both reactions could occur either via the
intermediate bridged iminium ion or through the acid-promoted
opening to the aldehyde and reclosure to the more thermody-
namically favored isomer. All of these reactions bode well for
synthetic applications of bridged hemiaminals having this [4.3.1]
ring system.
We next evaluated the stability of hemiaminals formed from
the addition of more sterically demanding organometallic
reagents. Thus, treatment of bicyclic amide 1a with MeLi
afforded amino ketone 8a (Table 2, entry 1). Not surprisingly,
an increase in steric hindrance at the hemiaminal carbon shifted
the equilibrium from the hemiaminal toward the aminoketone
species. Similarly, the reaction of 1a with secondary and tertiary
organolithiums furnished the corresponding amino ketones
(entries 4 and 5). Interestingly, in all cases, the addition stopped
at the ketone stage despite the presence of a large excess of
nucleophile. Resubjection of the aminoketone 8a to the reaction
conditions did not result in the formation of the tertiary alcohol,
suggesting that the steric hindrance around the quaternary carbon
prohibits further addition of the organometallic reagent. How-
ever, it is also possible that the initially formed addition product
persists in the reaction mixture prior to workup. While it is
known that planar tertiary amides react with organometallic
1
2
3
4
5
6
1e
1m
1e
1m
1e
1m
9a
10a
9b
10b
9c
10c
Me
Me
sec-Bu
sec-Bu
tert-Bu
tert-Bu
MeLi
MeLi
sec-BuLi
sec-BuLi
tert-BuLi
tert-BuLi
95
92
80
88
90
90
reagents,1a the high yields obtained in the transformations of
such sterically congested bridged lactams are noteworthy and
likely reflect the increased electrophilicity of the distorted amide
bonds.
Additions to Tricyclic Bridged Amides. The behavior of the
bicyclic hemiaminals corresponding to amino-ketones 8a-d
prompted us to examine the behavior of their tricyclic analogues.
We reasoned that the additional scaffolding afforded by the six-
membered ring attached to the bridged system could further
stabilize the hemiaminal form of the product.11 Indeed, exposure
of 1e to MeLi afforded hemiaminal 9a in good yield (Table 3,
entry 1). Increased bulk close to the reactive amide bond did
not influence the reaction, and 1m furnished the corresponding
hemiaminal product (entry 2). Remarkably, addition of a
secondary organolithium also provided stable hemiaminals
(entries 3 and 4). Ultimately, addition of tert-butyllithium finally
tipped the balance in favor of the ketone-containing product
(Table 3, entries 5 and 6).
Hemiaminals 9a-10b are some of the most sterically
hindered tetrahedral intermediates isolated to date.1a Although
it is possible that these structures exist in equilibrium with
the corresponding amino ketones, the predominance of the
hemiaminal form is secured by NMR and IR spectra.21,22 The
major species observed by NMR is characterized by a
hemiaminal carbon resonance at about 86-88 ppm in the
(19) For examples from recent literature, see: (a) Scott, M. S.; Luckhurst,
C. A.; Dixon, D. J. Org. Lett. 2005, 7, 5813–5816. (b) Lauzon, C.;
Charette, A. B. Org. Lett. 2006, 8, 2743–2745. (c) Nourry, A.;
Legoupy, S.; Huet, F. Tetrahedron Lett. 2007, 48, 6014–6018. (d)
Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008,
130, 17672–17673. (e) Beshore, D. C.; Smith, A. B. J. Am. Chem.
Soc. 2008, 130, 13778–13789. (f) Hsu, H. C.; Hou, D. R. Tetrahedron
Lett. 2009, 50, 7169–7171. (g) Enck, S.; Kopp, F.; Marahiel, M. A.;
Geyer, A. Org. Biomol. Chem. 2010, DOI: 10.1039/b917549k.
(20) For recent examples, see: (a) Yamazaki, N.; Suzuki, H.; Kibayashi,
C. J. Org. Chem. 1997, 62, 8280–8281. (b) Brummond, K. M.; Lu,
J. L. Org. Lett. 2001, 3, 1347–1349. (c) Hoffmann, H. M. R.;
Frackenpohl, J. Eur. J. Org. Chem. 2004, 429, 3–4312. (d) Yotphan,
S.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2452–
2453.
(21) (a) Nakashimi, T. T.; Maciel, G. E. Org. Magn. Reson. 1972, 4, 321–
326. (b) Hanisch, P.; Jones, A. J.; Casey, A. F.; Coates, J. E. J. Chem.
Soc., Perkin Trans. 2 1977, 1202–1208.
(22) Leonard, N. J.; Oki, M.; Brader, J.; Boaz, H. J. Am. Chem. Soc. 1955,
77, 6237–6239.
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Scheme 3. Organometallic Addition to Planar Analogues of
Bridged Amides
Scheme 4. Transannular Interaction in Bicyclic System
transannular interaction has been utilized extensively in con-
formationalanalysis,21b mechanisticphysical-organicchemistry,5a,b
total synthesis projects,24 and medicinal chemistry,5f,h,i,l-n the
majority of nitrogen-carbonyl transannular interactions reported
so far involve electrophiles placed directly on a ring or otherwise
conformationally restricted tropane-type structures. In contrast,
the currently studied one-carbon bridged amides would provide
reasonably flexible systems with the carbonyl moved one-carbon
away from the ring. The transannular hypothesis was also
supported by our previous finding that amino acids resulting
from hydrolysis of some of the one-carbon bridged amides are
subjected to strong proximity effects induced by the placement
of the reactive carboxylic acid and amine moieties on the
opposite sides of the medium-size rings.11
We were pleased to find that upon treatment of 8a with
MeOD-d4 a transannular N · · ·CdO interaction takes place
(Scheme 4). Thus, the carbon NMR spectrum of 8a in
chloroform exhibits a single set of signals, with a peak at 211
ppm corresponding to the methyl ketone. These observations
are consistent with a simple ketone-containing structure as
drawn. In methanol, the carbonyl peak is no longer present in
the 13C NMR, and other peaks are significantly broadened. We
ascribe these characteristics to an N · · ·CdO interaction afford-
ing a pseudotetrahedral hemiaminal-type carbon (8aa). Addition
of DCl to the methanol solution terminated the equilibrium,
affording a 9:1 mixture of protonated amino ketone 8ab and
hemiaminal 8ac. Upon dissolving 8a in DMSO-d6, a ca. 3:1
mixture of amino ketone and hemiaminal was formed, further
illustrating that the transannular closure is favored by increased
solvent polarity.5m
13C NMR. The ketone peak is not detected in the 13C NMR,
and only in two instances were very weak peaks correspond-
ing to the CO group observed in the IR (see below and
Supporting Information for additional discussion regarding
IR spectra). Although the analogous equilibrium is also
possible in the transannular amino tert-butylketones 9c and
10c, in these cases the open-form amino ketones seem to be
predominant as evidenced by 13C NMR and IR spectroscopy.
Overall, these results indicate that the steric contribution can
override the inherent stability of tetrahedral intermediates
provided by the scaffolding effects.
We wished to directly compare the reactivity of distorted and
planar amides in reactions with organometallic reagents. Thus,
a couple of fused amides (obtained as complementary products
to the bridged lactams in the intramolecular Schmidt reactions)8l
were subjected to the same conditions utilized for transforma-
tions of bridged lactams (Scheme 3). The reaction of fused
bicyclic amide 11 with MeLi afforded enamine 12.23 However,
the dehydration was not general, and addition of n-BuLi to 11
resulted in a complex mixture of products including the starting
amide, ketone, enamine, and alcohol. Similarly, the reaction of
a tricyclic fused amide 13 with MeLi led to an inseparable 3:1:1
mixture of enamine, ketone, and alcohol, with the subsequent
reduction affording amine 14. The very different results obtained
from fused versus bridged lactams emphasize the effect of the
amide bond geometry on the outcome of nucleophilic addition
reactions to amide bonds.
Observation of N · · ·CdO Interactions. We hypothesized that
the conformation of the 9-membered ring in 8a (Table 2, entry
1) should favor the placement of the reactive nitrogen and ketone
groupings on the same side of the ring, and thus permit
observation of transannular interactions between the amine and
carbonyl groups under appropriate conditions.5 It is generally
accepted that N· · ·CdO interactions between amines and
electrophilic ketones or aldehydes result in the formation of a
pseudotetrahedral hemiaminal-type carbon adopting a hybridiza-
tion state between sp2 and sp3 with a partial bonding being
formed between the reactive moieties.5b Although this type of
The transannular interaction between nitrogen and carbonyl
group in 8a could be independently detected by UV spectros-
copy (Figure 2).5e,m,n,25 When the UV spectrum of 8a was
measured in chloroform, a weak absorption with the maximum
at 241 nm was observed (ε ) 793 L mol-1 cm-1), corresponding
to the π f π*CdO transition. However, the spectrum of 8a in
MeOH exhibited a new and significantly more intense absorption
band appearing at a shorter wavelength (λmax ) 211 nm, ε )
(23) Quast, U.; Schneider, W. Liebigs Ann. Chem. 1982, 1501–1508.
(24) (a) Leonard, N. J.; Sato, T. J. Org. Chem. 1969, 34, 1066–1070. (b)
Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. A. J. Org. Chem.
1989, 54, 1548–1562. (c) Kim, G.; Chu-Moyer, M. Y.; Danishefsky,
S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30–39. (d) Fleming,
J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129,
9964–9975. (e) Fu¨rstner, A.; Korte, A. Chem.-Asian J. 2008, 3, 310–
318. (f) Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.; Garg,
N. K.; Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.; Ng,
F. W.; Overman, L. E. J. Am. Chem. Soc. 2007, 129, 11987–12002.
Figure 2. UV spectra in CHCl3 (-) and MeOH (- - -) of 8a.
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Proximity Effects in Nucleophilic Addition Reactions
A R T I C L E S
Scheme 5. Transformations of Bridged Amides
Figure 3. Transformations of adamantane-type bridged amides.
Scheme 6. Petasis Olefination of Lactam 1a
5688 L mol-1 cm-1), which could be ascribed to an nN f π*CdO
absorption. The change in absorption of 8a in methanol is similar
tothatobservedinearlierexamplesofN · · ·CdOinteractions.5e,m,n,25
Furthermore, a detailed examination of the IR spectra22 of a
series of bicyclic and tricyclic amino ketones and hemiaminals
8a-8d and 9a-10c also suggests the existence of the transan-
nular interaction in the nine-membered ring systems (see the
Supporting Information for additional discussion).
Although the above data are clearly consistent with the
presence of N · · ·CdO interaction, we cannot completely rule
out a dynamic bond breaking and forming event taking place
between the amino ketone and hemiaminal, with the latter
species being stabilized in polar solvents. This type of weak
covalent character of N · · ·CdO interaction, as contrasted to the
traditionally accepted nN f π*CdO homoconjugation,5b has also
been recently suggested in the literature.5l
It is noteworthy that this single bridged amide can be utilized
to monitor a continuum of change: from isolable hemiaminal
2a (stable tetrahedral intermediate) to amino ketone 8a (resulting
from the collapse of an analogous tetrahedral intermediate in
CDCl3) through an N · · ·CdO interaction (8aa, MeOH). This
picture also includes a progressive change from hemiaminals
9a-10b (stable tetrahedral intermediates) to amino ketones 9c
and 10c (collapsed tetrahedral intermediates).
As noted above, we hypothesized that the difference in
stability between the collapsed amino ketone 8a (Table 2, entry
1) and the stable hemiaminal 9a (Table 3, entry 1) could be
due to the increased scaffolding effect gained by the presence
of the additional cyclohexene ring in 9a. However, we also
considered that it could arise from a difference in distortion
parameters of the two parent amides. As previously established
by X-ray crystallographic analysis, the tricyclic lactam 1e is
characterized by Winkler-Dunitz distortion parameter,9 twist
angle, τ ) 51.5°,11 while a representative bicyclic lactam 1b is
slightly less distorted (τ ) 43.2°).26
Coe and co-workers (Figure 3).8i Interestingly, although in the
case of Coe’s amide a subsequent full reduction to the
corresponding amine was carried out, we were unable to reduce
17 under Wolff-Kishner conditions.
Furthermore, although Kirby demonstrated that perfectly
perpendicular 1-aza-2-adamantanone (τ ) 90.5°) undergoes
Wittig olefination (Figure 3),8h similar treatment of the
currently investigated amides did not result in enamines (only
starting amides were reisolated). However, the corresponding
bridged exocyclic enamine 18 could be conveniently prepared
from 1a utilizing Petasis reagent (Scheme 6).27 Although
some planar amides undergo olefination under Petasis condi-
tions, to the best of our knowledge this is the first example
of a direct olefination of a bridged bicyclic lactam with a
metalloorganic reagent. It is noteworthy that the oxatitana-
cyclobutane intermediate did not collapse with the opening
to the nine-membered ring system (in a fashion similar to
8a) and that the resulting enamine was stable to silica gel
chromatography.
Overall, these results clearly demonstrate that lactams
having a twist angle of ca. 50° display reactivity patterns
much closer to those expected for twisted rather than planar
amides. It is interesting to note that the bridged structures
resulting from nucleophilic addition reactions to these
distorted lactams (Scheme 5) are also stabilized through
proximity effects.
Conclusion
In summary, we have shown that tetrahedral adducts
formed from the addition of nucleophiles to one-carbon
medium-bridged twisted amides exhibit remarkable proxim-
ity-induced stability. These amides can serve as models to
delineate the transition from stable tetrahedral intermediates
to N · · · CdO interactions to unstable tetrahedral intermedi-
ates. In addition, this work provides the first experimental
evidence regarding degrees of the amide bond distortion that
mark the border between amide-like and ketone-like carbonyl
reactivity of lactams. Importantly, lactams characterized by
Reactions with Additional Nucleophiles. To investigate this
point, we subjected bicyclic and tricyclic bridged amides to
reactions with some oxygen and nitrogen nucleophiles, which
typically do not react with planar amides (Scheme 5). Thus,
reactions of tricyclic lactams with 1,3-propanediol and benzyl-
amine afforded bridged ketal 15 and bridged imine 16,
respectively, whereas fused bicyclic lactams were unreactive
under these conditions as expected. In addition, the tricyclic 1e
furnished bridged hydrazone 17. This particular reaction was
also performed to allow comparison of one-carbon bridged
lactams with an adamantane-type bridged amide reported by
(25) Leonard, N. J.; Oki, M. J. Am. Chem. Soc. 1955, 77, 6239–6240.
(26) Szostak, M. Ph.D. Dissertation, University of Kansas, 2009.
(27) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–
6394.
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for NMR assistance, and Dr. Reza Esfandiary and Dr. Sangeeta
Joshi (University of Kansas, Laboratory for Macromolecular and
Vaccine Stabilization) for help with UV measurements.
the midway rotated amide bonds undergo certain reactions
typically associated with ketones but not planar amides. Our
laboratory is currently investigating the chemistry of one-
carbon bridged amides and their derivatives, including
heteroatom-substituted tetrahedral intermediates.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the National
Institute of General Medical Sciences (GM-49093). We thank
Ruzhang Liu and Dr. Kevin Frankowski (University of Kansas)
for helpful discussions, Dr. Justin Douglas (University of Kansas)
JA909792H
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2084 J. AM. CHEM. SOC. VOL. 132, NO. 6, 2010