Total Synthesis and Characterization of 7-Hypoquinuclidonium Tetrafluoroborate and 7-Hypoquinuclidone BF3 Complex

Article abstract of DOI:10.1021/jacs.5b11750

Derivatives of the fully twisted bicyclic amide 7-hypoquinuclidone are synthesized using a Schmidt-Aubé reaction. Their structures were unambiguously confirmed by X-ray diffraction analysis and extensive spectroscopic characterization. Furthermore, the stability and chemical reactivity of these anti-Bredt amides are investigated. 7-Hypoquinuclidonium tetrafluoroborate is shown to decompose to a unique nitrogen bound amide-BF₃ complex of 7-hypoquinuclidone under anhydrous conditions and to react instantaneously with water making it one of the most reactive amides known to date.

Full text of DOI:10.1021/jacs.5b11750

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Article
Total Synthesis and Characterization of 7-Hypoquinuclidonium
Tetrafluoroborate and 7-Hypoquinuclidone BF3 Complex
Marc Liniger, David G VanderVelde, Michael K. Takase, Mona Shahgholi, and Brian M. Stoltz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11750 • Publication Date (Web): 29 Dec 2015
Downloaded from http://pubs.acs.org on December 29, 2015
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Journal of the American Chemical Society
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Total Synthesis and Characterization of 7-
Hypoquinuclidonium Tetrafluoroborate and 7-
7
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Hypoquinuclidone BF Complex
3
†
Marc Liniger, David G. VanderVelde, Michael K. Takase, Mona Shahgholi, and Brian M. Stoltz*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, Unit-
ed States
ABSTRACT: Derivatives of the fully twisted bicyclic amide 7-hypoquinuclidone are synthesized using a Schmidt-Aubé re-
action. Their structures were unambiguously confirmed by X-ray diffraction analysis and extensive spectroscopic character-
ization. Furthermore, the stability and chemical reactivity of these anti-Bredt amides are investigated. 7-hypoquinuclidonium
tetrafluoroborate is shown to decompose to a unique nitrogen bound amide-BF complex of 7-hypoquinuclidone under
3
anhydrous conditions and to react instantaneously with water making it one of the most reactive amides known to date.
also proposed as an intermediate in a model system to-
ward the synthesis of perophoramidine. Most recently,
INTRODUCTION
9
The importance of the amide bond cannot be overstat-
the structure, energetics and protonation of 7-
hypoquinuclidone 4 were investigated by DFT calcula-
1
2
ed. Typical amides are planar structures, however, am-
ide bonds can be highly twisted such as in bicyclic bridge-
1
0
tions and the molecule has been suggested to be too
3
1
0c
head lactams. The distortion of the orbitals from planarity
strained to be isolated.
2
and the pyramidalization of the nitrogen from sp toward
3
3,4
sp dramatically affect the stability and reactivity of anti-
RESULTS AND DISCUSSION
5
Bredt amides. In 2006, our group published the first un-
Based on the knowledge and experience in our research
group with the synthesis of 2-quinuclidonium tetrafluorob-
orate 1, we proposed a synthesis of 7-hypoquinuclidone 4
using an intramolecular Schmidt-Aubé reaction leading
to ketoazide 8 as the key fragment (Scheme 1).
n-BuLi,
ambiguous synthesis and characterization of 2-
quinuclidonium tetrafluoroborate 1 (Figure 1). Most re-
cently Kirby and co-workers reported on the synthesis and
characterization of the “most reactive” twisted amide, an
6
1
1
7
1
-aza-2-adamantone HBF salt 2, which provoked us to
4
THF,
°C → rt, 16 h
explore the synthesis of an even more reactive amide.
NNMe
2
O
0
TsCl, NEt3
H
N
BF4
Br
BF4
OH
CH
2 2
Cl ,
OTBS
O
O
0
°C → rt, 3 h
then 2 M HCl,
rt, 1 h
6
N
H
5
(93% yield)
O
(45% yield)
1
2
O
O
NaN
3
TFA, TfOH
COOH
DMF,
2 2
CH Cl ,
38 °C, 18 h
free flame
N3
OTs
7
0 °C, 2 h
7
8
N
(87% yield)
N
H
COOMe
3
4
O
1) MeOH, SOCl
2
Ts
N
rt → 55 °C, 18 h
+
Figure 1. Stoltz’s 2-Quinuclidonium tetrafluoroborate (1), Kir-
by’s “most reactive amide“ 2 and Hall’s attempted synthesis
of 7-hypoquinuclidone 4 from piperidine-4-carboxylic acid (3).
2) TsCl, NEt
DMAP, CH
0 °C → rt, 5.5 h
3
,
N
H
N
COOMe
2
2
Cl ,
Ts
10
not observed
4
•H+
9
(56% yield 3 steps)
Of interest to us was a 1958 paper, in which Hall failed
to synthesize 7-hypoquinuclidone 4 by heating piperidine-
Scheme 1. Synthesis of protected piperidine 4-carboxylic
acid methylester 9 – first proof for the existence of 7-
hypoquinuclidone 4.
4
-carboxylic acid (3) in a free flame (Figure 1). Instead,
8
sublimation of the amino acid was observed. The highly
strained structure of a [2.2.1] bridged bicyclic lactam was
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Page 2 of 7
Synthesis. The synthesis commenced from literature
known cyclobutanone N,N-dimethylhydrazone 5 , which
of product 4!BF . In contrast, the catalytic amount of acid
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
12
was consumed instantaneously with concomitant gas evo-
lution and precipitation of a solid. Thereafter, the reaction
did not proceed any further without adding a stoichio-
was alkylated with TBS protected 2-bromoethanol
13,14
(
Scheme 1).
The corresponding intermediate was fully
deprotected under acidic conditions to afford hydroxy ke-
tone 6 in 45% yield. Tosylation of the alcohol and substitu-
tion with sodium azide gave access to substrate 8 for the
intramolecular Schmidt-Aubé reaction. Since it was uncer-
metric amount of HBF (two equivalents in total). After stir-
4
ring overnight, we isolated instead of 4!BF3 the hydro-
lyzed amino acid 11 as the major product (73%) along
with 15% of 4!HBF4 and a third unknown species (ca.
+
1
20
tain, if this highly strained and fully twisted lactam 4!H
12%) according to H-NMR spectroscopy. When the
spectrum was recorded again the next day, the later two
species had converted to 11 in a quantitative fashion. At
would even exist, we decided to solvolyze this hypothetical
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
intermediate 4!H in situ with methanol as the nucleo-
phile. Moreover, the reaction was performed under Fischer
esterification conditions to ensure protection of the corre-
this point, it was still unclear how 4!BF was formed, but
3
we gained first evidence for the inherent instability of
+
sponding amino acid, in case 4!H would have been hy-
4!HBF4 toward hydrolysis in dry CD CN leading to the
3
drolyzed with traces of water. Thus, treatment of keto-
expected hydrolysis product isonipecotic acid tetra-
fluoroborate (11).
15
azide
8
with triflic acid
followed by solvoly-
sis/esterification with methanol and tosyl protection of the
amine furnished N-tosyl piperidine 4-carboxylic acid me-
thyl ester (9) in 56% yield over 3 steps after column chro-
Proof of Structure and Spectroscopic Data. 7-
Hypoquinuclidonium tetrafluoroborate (4!HBF ) was iso-
4
lated as a stable, colorless solid, which can be stored in a
16
matography. It should be noted that the corresponding
−
40 °C freezer of a nitrogen filled glovebox for several
protected azetidine 10 was not observed at all (it would
originate from migration of the other single bond in the
weeks without decomposition. However, as soon as the
solid is dissolved in any rigorously dried solvent, decom-
position starts immediately, even upon handling in the dry
17
Schmidt-Aubé reaction).
With
a
first proof for the existence of 7-
atmosphere of a glovebox (N ). For this reason, all of our
2
hypoquinculidone in hand, ketoazide 8 was treated with
tetrafluoroboric acid in diethylether, which led to immedi-
ate gas evolution and precipitation of a colorless solid
97% mass recovery). NMR experiments revealed the
presence of three species in a 77:15:12 ratio: the proto-
nated amide 7-hypoquinuclidonium tetrafluoroborate
attempts failed to grow single crystals of 4!HBF via pre-
4
cipitation, recrystallization or vapor diffusion method be-
tween −40 °C and 23 °C. Fortunately, decomposition was
(
slow enough to characterize 4!HBF spectroscopically in
4
1
11
19
13
14
CD CN solution by multinuclear H-, B-, F-, C-, N-,
N-NMR spectroscopy in a J. Young NMR tube and as a
3
15
4
!HBF , the hydrolysis product 11 and, unexpectedly,
4
solid by attenuated total reflectance infrared spectroscopy
(ATR-IR, Table 1). By contrast, 4!HBF4 was hydrolyzed
instantaneously in the matrix of the fast atom bombard-
ment high-resolution mass spectrometer (FAB-HRMS) and
in the electrospray ionization chamber (ESI) of a linear ion
trap mass spectrometer (LTQ-CID-MS). The mass spectra
for 4!HBF4 were identical to those recorded for the hy-
drolysis product 11. A very characteristic 1:1:1 triplet at
the BF complex of 7-hypoquinuclidone 4!BF (Scheme
3
3
2
).
COOH
O
O
O
HBF4
+
+
Et2O,
°C → rt,
N
N3
N
N
H2
0
F B
3
H
1
h
BF4
8
BF4
(
97% mass
+
1
4
•HBF4
11
4•BF3
7.76 ppm was observed for the NH group in the H-NMR
recovery)
1
14
spectrum of 4!HBF (Figure 2) showing a H- N coupling
4
Scheme 2. Total synthesis of 7-hypoquinuclidonium tetra-
fluoroborate 4!HBF4 and 7-hypoquinuclidone BF3 complex
!BF3.
(J = 63 Hz, I = 1, Table 1). This indicated a highly symmet-
ric environment around the nitrogen, since otherwise the
1
14
4
H- N splitting pattern would not be resolved due to sig-
2
1
nificant quadrupolar line broadening.
Since the formation of 4!BF3 was at first mysterious
and somehow unexpected, we were wondering, if traces
of BF3 etherate are present in our commercial 50-54%
HBF4 solution, which would catalyze the Schmidt-Aubé
1
8
reaction. The inherent instability of HBF in acidic solu-
4
tions was further supported by voltammetric investiga-
tions, which indicated decomposition of HBF to a BF -
4
3
1
9
solvent complex and HF. To check this hypothesis, ke-
toazide 8 was subjected to two equivalents of BF3
etherate instead of HBF with the ultimate goal to selec-
4
tively prepare 4!BF . However, neither gas evolution nor
3
consumption of the starting material was observed, even
at room temperature. Subsequently, a catalytic amount of
HBF4 was added with the idea that the proton of the
Brønsted acid would be formally released after formation
1
Figure 2. Detail of the H-NMR spectrum of 4!HBF showing
4
the distinctive 1:1:1 triplet of the protonated amide.
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1
Table 1. Selected spectroscopic properties for twisted amides 4!HBF4 and 4!BF3 and for the hydrolysis
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
product isonipecotic acid tetrafluoroborate (11).
a
Compound
4!HBF4
4!BF3
−
11
1
1
1
δ H of NH
7.76 (t, J
174.7
= 63 Hz)
6.90-6.12 (m, J
169.7
= ~55 Hz)
1H14N
x
1H14N
13
δ C of C=O
179.8
1
1
1
δ B
−1.2 (s)
−0.3 (q, J1
= 13.8 Hz)
= 13.9 Hz)
−1.2 (s)
1B19F
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
1
δ F
−151.3 (s)
−154.9 (q, J1
−151.2 (s)
9F11B
1
4
1
1
δ N
34.8 (d, J
= 62.8 Hz)
39.3 (s)
−4.9 (m, J
= not resolved)
14N1H
14N1H
1
5
b
1
1
c
δ N
78.6 ( J1
= ~88 Hz)
−
38.8 ( J
= ~77 Hz)
15N1H
5N1H
-
1
d
d
e
IR, νmax C=O, cm
1877
1860
1814
a
b
All NMR spectra were recorded in CD CN. Due to the low abundance of this isotope, the chemical shifts and coupling con-
3
1
15
1
15
15
c
2
stants were determined by H- N and H{ N}- N correlation experiments. A vicinal proton coupling constant of J1H1H
1
=
d
e
0.8 Hz was observed. Measured using an ATR-IR in an argon filled glovebox. Neat film on a NaCl plate.
These findings for 4!HBF4 were further confirmed by
nitrogen = blue, boron = pink, fluorine = yellow, carbon = dark
gray, hydrogen = white).
1
4
15
the observed doublets in the N- and N-NMR spectra
(
4
Table 1). The carbonyl infrared absorption band of
!HBF4 was observed at 1877 cm (ATR), which is the
In all our attempts to crystallize the protonated twisted
amide 4!HBF , we could only isolate crystals of the BF3
complex 4!BF , which apparently is the more stable
compound of the two amides (Figure 3). To our
knowledge, the BF3 complex of 7-hypoquinuclidone
!BF3 is the first and only nitrogen bound BF -amide
3
-
1
4
highest value we have ever observed for an organic mole-
cule, even higher than acid chlorides or anhydrides. This
value suggests a rather short and strong C=O bond in a
highly strained molecule. These conclusions were in line
3
4
with our DFT calculations for the structure of 4!HBF (see
4
complex reported to date. A single molecule of 4!BF3
2
2
Table 21 in the SI). Moreover, since we did not observe
any other C=O bands nor overlapping IR signals originat-
ing from the other two species (4!BF3 and 11), the rec-
was observed in the unit cell of the crystal with a high de-
gree of symmetry (mirror plane through the F-B-N-C=O
axis). The compound clearly belongs among the most
twisted amides with a torsion angle τ of 90.0°. The nitro-
gen is highly pyramidalized with an out-of-plane parameter
χN of 69.8°, while the carbonyl carbon is exactly planar
and sp hybridized (χ = 0.0°). The observed length of the
N-C(O) bond is 1.526 Å, 1.186 Å for the C=O bond and
.606 Å for N-B bond, respectively. These parameters
were all in close agreement to the calculated structure of
4!BF (see Table 21 in the SI and compare with parame-
orded IR spectrum of 4!HBF was evidence for high puri-
4
ty of the isolated crude solid after the reaction. The ob-
1
served mixture in the H-NMR spectrum of 4!HBF4,
4!BF3 and 11 (Scheme 2) most likely resulted from de-
2
C
composition by dissolving the solid in CD CN and in the
3
time until the NMR spectra were recorded.
1
A single crystal of 4!BF3 suitable for X-ray diffraction
analysis was grown over four weeks by slow diffusion of
diethyl ether into a solution of the crude twisted amide
3
ters of other twisted amides and more calculated struc-
4
!HBF in acetonitrile at −40 °C in the glove box (N ). The
tures). Selected spectroscopic parameters of 4!BF3 are
4
2
13
crystal structure of 4!BF is depicted in Figure 3.
summarized in Table 1. The C chemical shift of the car-
3
bonyl group in 4!BF3 is 5 ppm more downfield than in
!HBF , which is also true for the F chemical shift at
154.9 ppm. In the later case, the J coupling to B (I =
/2) was observed as a 1:1:1:1 quartet with a coupling
constant of 14 Hz. The reverse coupling to F (I = ½)
was visible at −0.3 ppm as a 1:3:3:1 quartet in the B-
NMR spectrum, however without any coupling to N.
The carbonyl stretching vibration for 4!BF was observed
at 1860 cm , which is a slightly lower frequency than for
!HBF . This trend is in line with a slightly longer C=O
19
4
−
3
4
1
11
23
19
1
1
1
4
24
3
-
1
4
4
bond for 4!BF3 than for 4!HBF4 according to our DFT
calculations (see Table 21 in the SI).
The formal hydrolysis product of 4!HBF , isonipecotic
4
Figure 3. X-ray structure of 7-hypoquinuclidone BF complex
3
acid tetrafluoroborate (11), was fully characterized by
spectroscopic methods (Table 1) and the structure was
unambiguously confirmed by X-ray diffraction analysis (see
4
!BF3 (ellipsoids at the 50% probability level, oxygen = red,
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the SI). As for the protonated twisted amide 4!HBF , spin min, 84 μM,
Page 4 of 7
7-
7
5
equiv D O, Figure 1),
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
14
1
15
couplings of H- N and H- N were observed with cou-
pling constants of 55 Hz and 77 Hz, respectively. Remark-
ably, the C=O IR stretching frequency at 1814 cm (NaCl)
hypoquinuclidonium tetrafluoroborate 4!HBF4 is now the
most reactive twisted amide prepared to date. In addition,
4!HBF decomposed in dry CD CN with a half-life of 119
-1
4
3
was rather high for a carboxylic acid.
minutes (117 μM). At the same time, saturation growth of
the BF complex 4!BF3 was observed over time, which
strongly indicated that 4!BF3 is indeed formed from
Chemical Behavior. As described earlier in this pa-
3
per, the protonated amide 4!HBF was much more sen-
4
4
!HBF4 in dry CD CN solution. It should be noted that
sitive to nucleophiles than the BF3 complex 4!BF3.
!HBF4 decomposed very quickly in solution, even in
rigorously dried solvents and with careful handling in the
glovebox. For this reason, the NMR spectra of dissolved
3
several other unidentified species were observed together
4
with 4!BF . However, amino acid 11 was not detected at
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
all due to the absence of water.
4
!HBF had to be recoded as fast as possible, since the
When the twisted amides 4!HBF4 and 4!BF and the
4
3
signals corresponding to 4!HBF disappeared very quick-
ly and several new species were formed over time. In con-
amino acid 11 were characterized by FAB-HRMS, we
found identical spectra due to fast hydrolysis in the matrix,
but also a common dehydration fragment with m/z 112.1
4
trast, solutions of the corresponding BF complex 4!BF
3
3
+
were fairly stable according to NMR spectroscopy. This
raised the question, if the BF complex 4!BF is the de-
composition product of the very labile amide 4!HBF4 in
corresponding to the protonated twisted amide 4!H or
its ring-chain tautomer as an oxocarbonium ion (Scheme
4). Since we previously observed dehydration of the hy-
drolyzed twisted amide 1 (Figure 1) via collision induced
3
3
dry solution, which would also explain, why we could grow
6
b
crystals of 4!BF out of a solution of 4!HBF .
dissociation (CID), this raised the question if 11 was de-
3
4
+
hydrated to 4!H by FAB ionization in the matrix or in the
To answer these questions, we studied the decomposi-
tion and reactivity of both twisted amides 4!BF3 and
gas phase. To investigate this, we isolated the ammonium
ion of 11 with m/z 130.1 in the ion trap of the LTQ-MS.
Upon collisional excitation (MS -CID), we did indeed ob-
serve dehydration giving an ion 4!H with m/z 112.1 in
the mass spectrum (see the SI for the spectra). When iso-
lation and excitation of 4!H was continued in a multi-
stage MS experiment (MS ), a formal loss of CO (M-28)
corresponding to an ion with m/z 81.4 was observed.
4
!HBF4 in CD CN in the presence or absence of D O
3
2
2
1
over time using a series of H-NMR measurements with
+
1
3
,3,5-trichlorobenzene as the internal standard (Scheme
, see the SI for more details).
+
COOD
O
3
D O
2
+
complex mixture
N
t1/2 = 87 min
N
D
O
F B
2
COOH
FAB-HRMS
or
O
3
BF4
11
LTQ-CID-MS
4•BF3
or
m/z 112.1
N
COOD
-H O
O
2
N
H
N
H
H
2
BF4
D O
2
1
1
4•H+
+
other species
N
t1/2 = < 1 min
N
H
D2
COOH
COOH
O
BF4
BF4
GC-MS
up to 300 °C
4•HBF4
11
or
m/z 112.1
N
-
H O
O
O
N
N
2
H
H
2
BF4
Boc
12
dry CD CN
3
4•H+
+
other species
1
1
N
H
N
t1/2 = 119 min
F B
3
BF4
Scheme 4. Gas phase and thermal reactivity of isonipectotic
acid derivatives.
4
•HBF4
4•BF3
Inspired by Kirby’s observation for thermal cyclization to
adamantane type twisted amides in the gas phase, we
attempted to cyclize amino acid 11 and the commercially
available Boc protected derivative 12 by gas chromatog-
raphy (Scheme 4). However, all attempts failed and no
ions were observed at all.
7
Scheme 3. Reactivity for 4!HBF and 4!BF in solution and
determination of their half-lives.
4
3
4
!BF3 was fairly stable in wet CD CN with a half-life of
3
8
7 minutes (9.6 equivalents of D O, 10.6 μM) yielding a
2
complex mixture of products along with amino acid 11
Definition of Bending Angle ξ. We observed signifi-
cant bending of the carbonyl oxygen towards the nitrogen
in the crystal structure of 4!BF3 (Figure 3) and we found
that this phenomenon was significantly underestimated in
our calculated structure of 4!BF (see Table 21 in the SI).
Since there wasn’t any parameter available in the literature
(
Scheme 3). By contrast, the protonated amide 4!HBF4
was hydrolyzed instantaneously upon addition of 5 equiva-
lents of D O (t = <1 min, 87.4 μM) to give amino acid 11
as the major product. Compared to the half-lives of 2-
quinuclidonium tetrafluoroborate 1 (t1/2 = 135 min, 84 μM,
2
1/2
3
6a
5
equiv) and Kirby’s “most reactive amide“ 2 (t1/2 = 8.4
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to describe C=O bending, we introduced a C=O bending
an addition to the already existing Dunitz-Winkler parame-
ters. Looking ahead, the limits are still open for the syn-
thesis of more or less reactive but structurally unique
twisted amides.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
angle ξ, which is defined as the deviation of the imaginary
CCN angle bisector (Figure 4). Mathematically, ξ can be
calculated with the bond path angles CCN, OCC and
25
OCN: ξ = ((360°-CCN)/2-OCN. A positive value means
METHODS
bending toward the nitrogen and a negative one bending
into the opposite direction. For the crystal and the calcu-
lated structure of 4!BF3, we observed ξ values of 5.8° and
Standard methods were used for the preparation, isola-
tion, and analysis of all new compounds (for experimental
details and complete characterization see the SI).
4
.5°, respectively.
Preparation of 4!HBF4 and Crystallization of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ξ
4
!BF3 from keto azide 8. To a solution of 8 (52.0 mg,
O
O
CCO
OCN
0.37 mmol, 1.0 equiv) in Et O (0.75 mL) was added at
2
σ(C-C)
σ*(C-N)
0
°C HBF (0.10 mL, 0.71 mmol, 1.9 equiv, 50-54% wt/wt
4
in Et O). Gas evolution was observed immediately. After
2
stirring for 1 h at room temperature, the starting material
was fully consumed and a colorless precipitate had been
formed. The solvent was decanted off with a syringe under
C
N
C
N
CCN
argon. The solids were washed with Et O (3 x 0.8 mL) and
2
Figure 4. Definition of the bending angle ξ and the dominant
orbital interactions of the p-type lone pair of the C=O oxygen.
dried under high vacuum to afford crude 4!HBF
(72.0 mg, 97% mass recovery) as a colorless solid. Slow
4
diffusion of Et O into a solution of the crude product in
2
In 1985, Bürgi and Schmidt investigated C=O bending
in lactones and lactams for the first time based on X-ray
acetonitrile at −40 °C over four weeks yielded one single
crystal of 4!BF (2.0 mg, 3%) as a colorless needle.
26
3
structures and molecular orbital calculations. An anomer-
ic effect was proposed to explain this phenomenon, which
involves destabilizing interactions of the p-type lone pair at
oxygen with the bonding σ(C-C) orbital and favorable over-
lap with the antibonding σ*(C-N) orbital (Figure 4). Thus,
C=O bending will reduce the former interaction and in-
ASSOCIATED CONTENT
Experimental procedures, characterization data, crystallo-
graphic information files, calculated geometries, and details of
kinetic measurements. This material is available free of charge
via the Internet at http://pubs.acs.org.
26
crease the later one. At the same time, C=O bending is
an early sign of C-N bond breakage leading to an oxocar-
AUTHOR INFORMATION
Corresponding Author
+
bonium ion similar to 4!H (Scheme 4) with concomitant
26
C-N bond elongation. In line with our own data (see Ta-
*
stoltz@caltech.edu
Present Address
Givaudan Schweiz AG, Fragrances S&T / Ingredients Re-
ble 21 in the SI), significant deviations of calculated ξ val-
ues were observed compared to X-ray structures by Bür-
26
10c, 27
gi and others.
†
Since C=O bending is a significant deformation of the
amide bond in anti-Bredt lactams and an additional meas-
ure for their stability, we suggest to use the Bürgi-Dunitz-
Winkler parameters (χ , χ , τ, ξ) to describe twisted am-
search, Ueberlandstrasse 138, CH-8600 Dübendorf, Switzer-
land
Notes
C
N
The authors declare no competing financial interest.
ides in the future.
ACKNOWLEDGMENT
CONCLUSIONS
The authors wish to thank NIH-NIGMS (R01GM080269),
Amgen, the Gordon and Betty Moore Foundation, the Caltech
Center for Catalysis and Chemical Synthesis, and Caltech for
financial support. M.L. thanks the Swiss National Science
Almost 60 years after Hall’s first attempt to prepare 7-
8
hypoquinuclidone 4, we have successfully accomplished
the first total synthesis and complete characterization of
the protonated twisted amide 4!HBF4 and its BF com-
3
Foundation
(SNSF)
for
a
postdoctoral
fellowship
plex 4!BF . The use of a Schmidt-Aubé reaction proved
3
(
P2EZP2_148751). Jonathan Rittle is acknowledged for assis-
6
a
again to be key for success. Moreover, the stability and
reactivity of both 4!HBF4 and 4!BF3 were thoroughly
investigated in solution and in the gas phase. These stud-
ies revealed that 4!HBF4 is to our knowledge the most
reactive amide prepared to date with a half-life of less than
one minute in the presence of water. The reverse reaction
tance with the ATR-IR and the Peters group for using their
equipment. We are indebted to Dr. Kousouke Tani and Dr.
Michael Krout for taking the first steps in creating the twisted
amide project and for establishing their synthesis, isolation
and crystallization.
+
REFERENCES
to 4!H was rendered possible in the gas phase by formal
dehydration of isonipecotic acid 11 using FAB or CID ex-
citation. Since C=O bending contributes to the stability of
(1) Greenberg, A.; Breneman, C. M.; Liebman, J. F., Eds. The
Amide Linkage: Structural Significance in Chemistry, Biochemistry
and Material Science; John Wiley & Sons: Hoboken, 2003.
2
6
twisted amides and is still difficult to predict by DFT cal-
10c, 26, 27
culations,
a novel bending angle ξ was defined as
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Journal of the American Chemical Society
Page 6 of 7
(
2) (a) Pauling, L.; Corey, R. B.; Branson, H. R. Proc. Natl.
2
(17) Shifting of the alkyl group antiperiplanar to the N leaving
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Acad. Sci. U.S.A. 1951, 37, 205. (b) Pauling, L.; Corey, R. B. J.
Am. Chem. Soc. 1952, 74, 3964. (c) Corey, R. B.; Pauling, L.
Proc. Roy. Soc. B 1953, 141, 10.
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Soc. 2007, 129, 2766. (b) Szostak, M.; Aubé, J. Org. Biomol.
Chem. 2011, 9, 27. (c) Gutierrez, O.; Aubé, J.; Tantillo, D. J. J.
Org. Chem. 2012, 77, 640.
(
3) For the most recent review about the synthesis and reactivi-
ty of bridged lactams see: Szostak, M.; Aubé, J. Chem. Rev.
3
(18) For BF etherate mediated Boyer-Schmidt-Aubé reactions
2
5
013, 113, 5701.
4) (a) Hall, H. K., Jr.; El-Shekeil, A. Chem. Rev. 1983, 83,
49−555. (b) Clayden, J. Nature 2012, 481, 274. (c) Aubé, J.
see: (a) Gracias, V.; Milligan, G. L.; Aubé, J. J. Am. Chem. Soc.
1995, 117, 8047. (b) Gracias, V.; Frank, K. E.; Milligan, G. L.;
Aubé, J. Tetrahedron 1997, 53, 16241. (c) Forsee, J. E.; Aubé,
J. J. Org. Chem. 1999, 64, 4381. (d) Smith, B. T.; Gracias, V.;
Aubé, J. J. Org. Chem. 2000, 65, 3771. (e) Desai, P.;
Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan, G. L.;
Aubé, J. J. Am. Chem. Soc. 2000, 122, 7226. (f) Lertpibulpanya,
D.; Marsden, S. P. Org. Biomol. Chem. 2006, 4, 3498. (g) Shin-
de, M. V.; Ople, R. S.; Sangtani, E.; Gonnade, R.; Reddy, D. S.
Beilstein J. Org. Chem. 2015, 11, 1060.
(
Angew. Chem. Int. Ed. 2012, 51, 3063.
(5) For the definition of amide bond deformation see: Dunitz, J.
D.; Winkler, F. K. Acta Cryst. 1975, B31, 251.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
6) (a) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (b) Ly, T.;
Krout, M.; Pham, D. K.; Tani, K.; Stoltz, B. M.; Julian, R. R. J.
Am. Chem. Soc. 2007, 129, 1864.
(
7) Komarov, I. V.; Yanik, S.; Ishchenko, A. Y.; Davies, J. E.;
Goodman, J. M.; Kirby, A. J. J. Am. Chem. Soc. 2015, 137,
(19) Bontempelli, G.; Seeber, R.; Zecchin, S.; Schiavon, G. J.
Electroanal. Chem. 1976, 73, 295.
9
26.
(8) Hall, H. K., Jr. J. Am. Chem. Soc. 1958, 80, 6412.
(9) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
068.
10) (a) Morgan, J.; Greenberg, A. J. Chem. Thermodynamics
014, 73, 206. (b) Szostak, R.; Aubé, J.; Szostak, M. Chem.
(20) A characteristic singlet at 9.28 ppm was observed in the
1
crude H-NMR spectrum (500 MHz, CD
3
CN).
5
2
(21) (a) Lehn, J.-M.; Franck-Neumann, M. J. Chem. Phys.
1965, 43, 1421. (b) Burgar, M. I.; St. Amour, T. E.; Fiat, D. J.
Phys. Chem. 1981, 85, 502.
(
Commun. 2015, 51, 6395. (c) Szostak, R.; Aubé, J.; Szostak, M.
J. Org. Chem. 2015, 80, 7905.
(
22) The calculated bond length for N-C(O) in 4!HBF4 is 1.613
Å, which is longer than in 4!BF3 (measured 1.526 Å and calcula-
(
11) Aubé, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113,
8965.
(12) Cyclobutanone N,N-dimethylhydrazone was prepared ac-
ted 1.534 Å, respectively).
19
10
(
23) Unresolved coupling of F to B (I = 3) was observed as
well (a septet would be expected). However, the minor signal was
cording to: Mino, T.; Masuda, S.; Nishio, M.; Yamashita, M. J.
Org. Chem. 1997, 62, 2633.
(
to: Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202.
(
-azido-2-iodoethane failed to give ketoazide 8 in one step, since
addition of the electrophile to the anion of 5 led to vigorous gas
evolution and immediate decomposition of the reaction mixture.
11
overlapping with the more intense peak originating from B cou-
pling (ca. 1/3 intensity of the major peak).
13) TBS protected 2-bromoethanol was prepared according
11
14
(24) The absence of B- N coupling is in line with heteronu-
clear NMR experiments on trimethylamine-boron trihalide com-
plexes: Hall Clippard, P.; Cooper Taylor, R. Inorg. Chem. 1969,
14) Alkylation of cyclobutanone N,N-dimethylhydrazone 5 with
8
, 2802.
25) The sum of the three bond path angles CCN, OCC and
OCN is 360°.
26) Nørskov-Lauritsen, L.; Bürgi, H.-B.; Hofmann, P.;
1
(
(
(
15) Neither gas evolution nor conversion was observed when
.5 equivalents of trifluoroacetic acid were used without any triflic
acid.
Schmidt, H. R. Helv. Chim. Acta. 1985, 68, 76.
(27) (a) Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987,
09, 5935. (b) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc.
993, 115, 6951.
1
1
1
(
16) Traces of the protected dimer and trimer of 9 were de-
tected by LC-MS in the crude reaction mixture (see the SI for the
spectra), which was an evidence for the polymerizability of 4.
Compare with reference (8).
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