Experimental and theoretical studies of a one-flask synthesis of 3H-1-benzazepines from 2-haloanilines and α,β-unsaturated ketones

Article abstract of DOI:10.1002/ejoc.200901468

3H-1-Benzazepines are prepared in one step from the reaction of 2-fluoro- or 2-chloroaniline and several aryl vinyl ketones. Enones 9a-c gave benzazepines 11a-c as expected, showing that alkyl substitution at C4 and C5 in the benzazepines is possible. However, enone 9d underwent decomposition due to conjugate addition of the 2-fluoroaniline, while enone 10 gave unsaturated imine 12 as the only product able to be isolated. The failure of unsaturated imine 12 to undergo cyclization may indicate that placement of an alkyl group at C3 of the benzazepines may not be possible. Isolation of by-products buttressed by a computational study verifies a postulated, multi-step process for benzazepine formation: a [1,5] sigmatropic shift in fluoroimine 3, addition elimination to give carbocation 15, formation of the unstable 5H-1-benzazepine 7, and acid-catalyzed isomerization to give the stable 3H-1-benzazepine 2. The calculations also indicate why unsaturated imine 12 fails to cyclize. NMR spectroscopic experiments show that the 3H-benzazepines undergo fast conformational exchange on the NMR time scale at room temperature except when there is an alkyl substituent at C5.

Full text of DOI:10.1002/ejoc.200901468

FULL PAPER
DOI: 10.1002/ejoc.200901468
Experimental and Theoretical Studies of a One-Flask Synthesis of
3H-1-Benzazepines from 2-Haloanilines and α,β-Unsaturated Ketones
Keith Ramig,*[a] Edyta M. Greer,*[a] David J. Szalda,[a] Rabail Razi,[a] Fahima Mahir,[a]
Nataliya Pokeza,[a] Wei Wong,[a] Benjamin Kaplan,[a] Joanne Lam,[a] Ayesha Mannan,[a]
Christopher Missak,[a] Dat Mai,[a] Gopal Subramaniam,[b] William F. Berkowitz,[b]
Prakash Prasad,[b] Sasan Karimi,[c] Ngai Hin Lo,[c] and Linas V. Kudzma[d]
Keywords: 1-Benzazepine / DFT calculations / Imine / Intramolecular addition-elimination / Variable-temperature NMR
spectroscopy
3H-1-Benzazepines are prepared in one step from the reac-
tion of 2-fluoro- or 2-chloroaniline and several aryl vinyl
ketones. Enones 9a–c gave benzazepines 11a–c as expected,
showing that alkyl substitution at C4 and C5 in the benz-
tion of by-products buttressed by a computational study veri-
fies a postulated multi-step process for benzazepine forma-
tion: a [1,5] sigmatropic shift in fluoroimine 3, addition elimi-
nation to give carbocation 15, formation of the unstable 5H-
azepines is possible. However, enone 9d underwent decom- 1-benzazepine 7, and acid-catalyzed isomerization to give
position due to conjugate addition of the 2-fluoroaniline,
while enone 10 gave unsaturated imine 12 as the only prod-
uct able to be isolated. The failure of unsaturated imine 12 to
undergo cyclization may indicate that placement of an alkyl
group at C3 of the benzazepines may not be possible. Isola-
the stable 3H-1-benzazepine 2. The calculations also indicate
why unsaturated imine 12 fails to cyclize. NMR spectroscopic
experiments show that the 3H-benzazepines undergo fast
conformational exchange on the NMR time scale at room
temperature except when there is an alkyl substituent at C5.
Introduction
The 1-benzazepine moiety is being found more and more
frequently in molecules of pharmaceutical interest.[1] Al-
though there are scattered accounts of 3H-1-benzazepines[2]
their syntheses are laborious and their chemistry has not
been well studied. A preliminary report from our labs[3] de-
scribed a new synthesis of 3H-1-benzazepines using a one-
flask procedure (Scheme 1). Acetophenone was heated with
one equivalent of 2-fluoroaniline, with azeotropic removal
of water, forming the imine 1.[4] Further heating yielded 2,4-
diphenyl-3H-1-benzazepine 2. We are aware of only one
other report[2c] of this kind of process, which gives very low
yields of benzazepines from two exotic highly fluorinated
aromatic amines and acetophenone.
Scheme 1.
We will disclose here new findings which will allow pro-
duction of a wider variety of 3H-1-benzazepines. Possible
mechanisms for benzazepine formation will be proposed,
based partially on new experimental data and calculations.
Also, fluxional behavior of the azepine ring will be studied
with NMR spectroscopic experiments.
From our previous work,[3] it appeared that only 2,4-di-
arylbenzazepines could be prepared, as both 4-methyl-2-
pentanone and propiophenone failed to give benzazepines
under the usual conditions. Also, the two aryl groups in the
cases which do work must perforce be identical to each
other. These circumstances lead to another limitation: The
3- and 5-positions will remain unsubstituted in every benza-
zepine. Herein we will show that the limitations are not as
severe as we had at first thought.
[a] Department of Natural Sciences, Baruch College of the City
University of New York,
17 Lexington Ave., New York, NY 10010, USA
Fax: +1-646-660-6201
E-mail: keith.ramig@baruch.cuny.edu
edyta.greer@baruch.cuny.edu
[b] Department of Chemistry and Biochemistry, Queens College of
the City University of New York,
65-30 Kissena Blvd., Flushing, NY 11367, USA
[c] Department of Chemistry, Queensborough Community College
of the City University of New York,
222-05 56th Ave., Bayside, NY 11364, USA
[d] Baxter Anesthesia and Critical Care,
Initial Mechanistic Hypothesis
95 Spring St., New Providence, NJ 07974, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901468.
The mechanism for benzazepine formation that we origi-
nally proposed[3] is shown in Scheme 2. After acid-catalyzed
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Scheme 2.
formation of imine 1, further heating may cause an aldol- fluoroaniline and an α,β-unsaturated ketone We have found
like condensation between two imines, giving unsaturated that dypnone (the self-aldol/dehydration product of aceto-
imine 3. Imines are known to undergo this kind of transfor- phenone) will react with two equivalents of 2-fluoroaniline
mation under similar conditions.[5] After proton transfer to give benzazepine 2 in good yield. Presumably the inter-
giving compound 4, further rearrangement produces inter- mediate in this process is imine 3.
mediate 5. This could undergo acid-catalyzed cyclization
accompanied by fluoride loss, giving cation 6, which rearo-
matizes to 5H-benzazepine 7 by proton loss. Finally, benz-
azepine 7 isomerizes to benzazepine 2.
We explored the possibility of varying the substituents
on the benzazepine skeleton, by using various dypnone de-
rivatives in the reaction. First, the aldols 8a–e were pre-
pared in 35–60% yields from the enol ethers of either 4Ј-
methylacetophenone or propiophenone, and a different
ketone (Scheme 3).[6] All the aldols were stable except for
8d, which partially dehydrated in the crude reaction mix-
ture. Then, the aldols 8a–d were dehydrated[7] uneventfully
to give enones 9a–d in 35–72% yields. Aldol 8e however,
gave the β,γ-unsaturated ketone 10 in 41% yield.
Treatment of the enones 9a–c and 10 with 1.5 to two
equivalents of 2-fluoroaniline and a catalytic amount of
pTsOH delivered 3H-1-benzazepines 11a–c in moderate
yields (Scheme 4). Enone 10 gave unsaturated imine 12 as
the only isolable product; the bulk of the crude reaction
mixture consisted of many unidentified products, none of
which appeared to be a benzazepine, judging by NMR spec-
troscopic analysis. Enone 9d gave a complex mixture of
products, with no evidence for the presence of benzazepine
11e. The only product able to be identified was a small
We have failed in attempts to isolate unsaturated imine
3, with which we had hoped to study the proposed conver-
sion to later intermediates and the benzazepine. All
attempts at heating simple imine 1 in order to bring about
the aldol-like condensation either gave no reaction, or with
longer heating or a higher temperature, caused conversion
to benzazepine 2. We will reveal here new experiments that
give strong evidence that the mechanism does indeed pro-
ceed through unsaturated imine 3, and will propose an al-
ternative mechanism upon which calculations have been
performed.
Results and Discussion
Generalization Studies
If the imine 3 from Scheme 2 is indeed an intermediate amount of benzazepine 11d.[3] We theorize that decomposi-
leading to the benzazepines, then it should be possible to tion of the enone is initiated by conjugate addition of 2-
prepare benzazepines using the imine formed from 2- fluoroaniline, resulting in a retro-aldol-like reaction. This
Scheme 3. (a) TMSCl, NaI, triethylamine, in CH3CN; (b) ketone [a: 4Ј-(trifluoromethyl)acetophenone, b: acetophenone, c: cyclohexanone,
d: acetone, e: 4Ј-methylacetophenone], TiCl4 in CH2Cl2; (c) TFAA, triethylamine, DMAP, in CH2Cl2.
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One-Flask Synthesis of 3H-1-Benzazepines
would yield 4Ј-methylacetophenone as one of the products,
which would react with remaining 2-fluoroaniline and give
benzazepine 11d. This taught us that the β position of the
enone needs to be sufficiently sterically hindered to avoid
side-reactions. Enone 9c, which is more hindered at the β
carbon than 9d, furnished benzazepine 11c in acceptable
yield.
Figure 1. An ORTEP drawing of 11b with thermal ellipsoid at 50%.
the yield of benzazepine is diminished by about 15% and
starting enone remains. The optimal amount appears to be
1.5 equiv.; the yield of benzazepine 11a improved from 44%
when two equivalents were used, to 56% when 1.5 equiv.
were used.
Scheme 4.
Benzazepine 11b gave crystals suitable for X-ray struc-
tural analysis. Intensity measurements and systematic ab-
sences were consistent with the monoclinic space group
P21/c and it was used for the solution and refinement of the
structure. The structure was solved by direct methods.[8]
The carbon atoms and nitrogen atom were refined using
anisotropic thermal parameters. Hydrogen atoms were lo-
An Alternative Mechanistic Hypothesis
In the preliminary communication,[3] we reported that 2-
cated on a difference Fourier map and refined with individ- chloroaniline failed to give benzazepine under conditions
ual isotropic thermal parameters. An empirical absorption where 2-fluoroaniline would. We have reinvestigated this re-
correction was applied using ABSOR.[9] A view of the sult, and have found that when the solvent is toluene at
structure is found in Figure 1 and crystallographic details reflux, 2-fluoroaniline is indeed more reactive towards dyp-
are provided in the Supporting Information. In the seven- none than 2-chloroaniline; in the former case, conversion to
membered ring, C2, C4, C6, and C7 form a best fit plane benzazepine is far along while in the latter case, little or no
with a RMS deviation of 0.02 Å (C3 is 0.9 Å below this benzazepine is formed. However, when the solvent is the
plane while N1 and C5 are each 0.4 Å above the plane). higher-boiling o-xylene at reflux, both anilines give a good
The phenyl ring labeled C21–C26 makes an angle of 31.3° yield of benzazepine. Building on this, we have been suc-
with this plane and the phenyl ring labeled C41–C46 makes cessful in preparing the chloro analog of fluoroimine 3,
an angle of 84.4° with the plane. There are two intermo- namely chloroimine 13 (Scheme 5). When chloroimine 13 is
lecular C–H···N hydrogen bonds[10] one between the hydro- heated at reflux in mesitylene, with or without the acid cata-
gen atom on C45 and the nitrogen atom on a symmetry- lyst, benzazepine 2 is formed. While this latter step does not
related molecule H45···N1A 2.74 Å with a C45–H45···N1A depend on the presence of pTsOH, we have performed the
(A = x, 0.5 – y, –0.5 + z) angle of 165° and the other C241– proper controls to show that formation of imine does re-
H241···N1B with a H241···N1B distance 2.902 Å and angle quire acid catalysis.
of 168° (B = 1 – x, –0.5 + y, 0.5 – z). We are aware of one
other report of the crystal structure of a related benzazep- without the presence of an extra equivalent of 2-chloro-
ine.[11]
aniline to neutralize the HCl that is presumably formed, is
The fact that imine 13 can be converted to benzazepine
Attempts were made to optimize the yield of the benz- also a significant finding. A mechanism that fits all the cur-
azepines. Initially it was thought that use of two equivalents rent data is presented in Scheme 6. The conversion of fluoro-
of 2-fluoroaniline was necessary, because when the starting imine 3 to enamine 4 could occur by a thermal [1,5] sigma-
ketone is acetophenone as in Scheme 2, little or no benz- tropic shift. Then, an addition-elimination process ensues.
azepine is formed without inclusion of the extra 2-fluoro- Enamine 4 gives ylide 14, which ejects a halide ion to give
aniline. But later we found that one equivalent is sufficient carbocation 15. We also considered an intramolecular [4+2]
when the starting material is a dypnone derivative, although cycloaddition of 4, which would give a ring-fused aziridine.
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Scheme 5.
The barrier height of TS4–14 is 26.5 kcal/mol and reaches
14 in a reaction that is endothermic by 21.3 kcal/mol. Both
activation energies are attainable in refluxing xylene. The
calculations also showed that an intramolecular [4+2] cyclo-
addition in 4, giving a tryclic aziridine, is highly unlikely as
the activation energy was found to be prohibitively high at
65.0 kcal/mol.[12]
Next, we sought to explain the failure of imine 12 to
cyclize. We investigated this system by taking points corre-
sponding to the proton transfer from fluoroimine syn-3 to
enamine 4, and cyclization of 4 shown in Scheme 7, replac-
ing the hydrogen atom at C-3 by a methyl group and reopti-
mizing. A different result from Scheme 7 was obtained,
Scheme 6.
At this point, we began a computational study, with the which is summarized in Scheme 8. After reoptimizing the
dual aim of verifying the mechanism of Scheme 6, and to structures, we found that, at the B3LYP/6-31G(d) level, the
explain the failure of imine 12 to undergo cyclization. proton transfer from imine 12 to yield 16 involves TS12–
Scheme 7 shows two steps of Scheme 6: (A) the proton 16. The barrier height of TS12–16 is 25.0 kcal/mol so the
transfer from fluoroimine syn-3 to fluoroamine 4 and (B) [1,5] sigmatropic proton shift between C5 and N1 is feasible
the cyclization of amine 4 to ylide 14. All the molecules under the reaction conditions. Then we attempted, but were
shown in Scheme 7 are structural isomers, thus we were able unable, to find a cyclization route to convert 16 to 17. We
to compare both processes on the same energy scale. We identified structure 16–17 that was characterized by the fre-
found that, at the B3LYP/6-31G(d) level, a 23.9 kcal/mol quency calculations as the third-order saddle-point due to
saddle point (TS3–4) connects 3 and 4 which represents a strong geometric distortion caused by the methyl group at
proton shift from C5 to N1. We chose the B3LYP/6-31G(d) C3 sandwiched between phenyl rings A and B. The struc-
combination of the method and the basis set because it per- ture 16–17 is located 55.1 kcal/mol above imine 12 and is
formed well in predicting the bond lengths and bond angles therefore unreachable under the applied experimental reac-
of 11b determined by X-ray analysis.[12] Next, a reaction tion conditions. So the problem appears to be steric interac-
path was computed for converting amine 4 to ylide 14.[13] tions between the methyl group at C-3 and the phenyl rings.
Scheme 7. A: Computed proton transfer between C5 and N1 of fluoroimine 3 and fluoroamine 4. B: cyclization of fluoroimine 4;
comparison on the same energy scale. Bond lengths are given in Å. Energies in parentheses calculated at the B3LYP/6-31G(d) level
include ZPE corrections.
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One-Flask Synthesis of 3H-1-Benzazepines
Scheme 8. A: Computed proton transfer from imine 12 to amine 16. B: Cyclization of amine 16. For the simplicity of calculations the
methyl group in the para position of ring B was eliminated in 12 and related computed structures. Energies include ZPE corrections.
We now turn to elucidating the rest of the mechanism of atom of 5H-isomer 7 and proton loss to give the 1H-isomer
Scheme 6. At the time of our initial study,[3] we supposed 18 (Scheme 9). This isomer then undergoes a similar pro-
the existence of 5H-benzazepine 7 without any supporting tonation/deprotonation sequence, delivering 3H-isomer 2.
experimental evidence. Careful inspection of the crude reac- (It is also possible that 1H-isomer 18 could be formed di-
tion mixture reveals the presence of 7, in a 1:12 ratio with rectly from carbocation 15 by loss of a proton from C5.)
1
the 3H-isomer 2 as judged by H NMR integration values While we have no direct evidence for the involvement of the
of the two singlets due to the methylene groups. Chromato- 1H-isomer 18, calculations show that it is the least stable of
graphic purification gave pure 5H-isomer 7. The two benz- the three (8.4 kcal/mol less stable than 2), followed by the
azepine isomers equilibrate in the presence of an acid cata- 5H isomer (2.0 kcal/mol less stable than 2), with the 3H
lyst. When either 5H-isomer 7 or 3H-isomer 2 is heated in isomer being the most stable (Figure 2). Hence the 1H iso-
xylene in the presence of a catalytic amount of pTsOH, a mer may be present in an amount too small to be easily
1:12 mixture of the two isomers results, favoring the 3H detected. Or, it is also possible that the site of initial proton-
isomer. We have also found that equilibration can occur ation of the 5H isomer could be C3, giving a benzylic cation
without the presence of added acid, albeit at a slower rate, which would give the 3H isomer directly by proton loss. It
and is almost squelched by addition of DMAP. These re-
sults point to acid catalysis by the glass surface of the reac-
tion flask. The possibility of interconversion of isomers 7
and 2 by two distinct series of [1,5] sigmatropic proton
shifts was ruled out by calculations. Our calculations
showed that the energy barrier corresponding to the se-
quence starting with the proton transfer from C5 to C2 is
very high, at 48 kcal/mol. In the case of the sequence that
begins with the proton transfer from C5 to N1 the acti-
vation barrier is 42.5 kcal/mol.[12] Therefore we favor a
mechanism which starts with protonation of the nitrogen Scheme 9.
Figure 2. Relative energies of 3H-1-benzazepine 2, 5H-1-benzazepine 7, 1H-1-benzazepine 18 calculated at B3LYP/6-31G(d).
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should be added that 2-substituted 5H-1-benzazepines are 2.21 ppm and 4.51 ppm, whereas the two allylic protons of
known to rearrange to give the more stable 3H-1-benzazep- the 5H-benzazepine split into two resonances at δ =
ines.[2b]
3.31 ppm and 3.87 ppm below –45 °C. The slight difference
in the chemical shifts of the allylic protons in the 5H-isomer
7 vs. the large difference in the 3H-isomer 2 may be ex-
plained by the differing orientations of the aryl groups
flanking the allylic protons.
NMR Spectroscopic Studies of the Benzazepines
Characterization of the benzazepines was initially ham-
pered by anomalies in their H NMR spectra. The two al-
1
lylic protons at C3 were observed as a broad singlet in
CDCl3 at room temperature in most of the benzazepines
shown in Schemes 1 and 4, with two exceptions. Since the
azepine ring is non-planar, one would expect the two pro-
tons to be non-equivalent and possibly give separate reso-
nances unless they exchange rapidly on the NMR time
scale. We were able to slow down the exchange rate by low-
ering the temperature and thus observe two separate signals
for each of the two allylic protons at C3 in all benzazepines.
Alkyl substitution at C5 appreciably slows the conforma-
tional change. For example, two separate broad allylic pro-
ton resonances were observed at room temperature for 11b
and 11c and they were confirmed by careful peak integra-
tion. The fact that all other benzazepines showed a single
resonance for the allylic protons at room temperature me-
ans that the conformational change in these cases is rela-
tively rapid, compared to benzazepines 11b and 11c. Of
particular mention is one of the allylic proton resonances
of 11b buried underneath the methyl signal at δ = 2.36 ppm.
This allylic signal was confirmed by integration as well as
through a C–H correlation experiment. Upon lowering the
temperature to –50 °C, the allylic resonances of 11b sharp-
ened and a geminal coupling of 12.0 Hz could be observed
(Figure 3). The geminal coupling could not be observed in
all the benzazepines because of exchange line broadening
even at the limiting temperature of –64 °C, the freezing
point of the CDCl3 solvent.
Conclusions
This new synthesis gives facile access to the rarely studied
3H-1-benzazepine ring system. Calculations back-up a pos-
sible mechanism for the transformation, in which an intra-
molecular addition-elimination to an aromatic ring com-
pletes ring closure. The scope and limitations will be studied
further, as will the factors which affect the equilibration of
1H-, 3H-, and 5H-1-benzazepines. Variable-temperature
NMR spectroscopic studies indicate that the substitution
pattern of the azepine ring affects its fluxional properties;
a thorough study bolstered by molecular mechanics calcula-
tions will be forthcoming.
Experimental Section
General: Dypnone was obtained from Frinton Laboratories, Inc.,
Vineland, New Jersey, USA, www.frinton.com. H and 13C NMR
1
spectra are referenced to tetramethylsilane. 19F NMR spectra are
referenced to CF3CO2H externally, set at –76.55 ppm.
Computational Methods: All calculations were carried out by
B3LYP[14] alongside with the 6-31G(d)[15] basis with
Gaussian 03.[16] Our B3LYP/6-31G(d) were successful in reproduc-
ing the values of bond lengths and bond angles available for benz-
azepine 11b through X-ray analysis.[12] The combination of the
B3LYP method and the 6-31G(d) basis set is know to reproduce
geometries in a variety of experimental systems.[17] All compounds,
except 16–17, were characterized as minima or maxima on the cor-
responding potential energy surface (PES) by the frequency calcu-
lations. Structure 16–17 was found to be the third order saddle
point. In addition to the analysis of the modes of the imaginary
frequencies, transition stuctures were confirmed by tracing the in-
trinsic reaction coordinate (IRC).[18] All reported energies include
unscaled ZPE corrections derived from frequency calculations. All
structures were viewed with GaussView software.[19]
2,4-Diphenyl-5H-1-benzazepine (7): The crude reaction mixture
containing a 1:12 mixture of benzazepines 7 and 2, prepared on a
13.5-mmol scale as described previously,[3] was stirred with 1%
EtOAc/hexanes (30 mL). The insoluble 3H-benzazepine isomer 2
was removed by suction filtration. The filtrate containing 5H-iso-
mer 7 was stirred again with 1% EtOAc/hexanes (10 mL), and the
supernatant was decanted, giving 832 mg of viscous amber oil
which solidified upon standing. This was triturated with hexane
(2 mL). The supernatant was pipetted off, and the solvent of this
was removed by rotary evaporation. The resulting 343 mg of yellow
oil contained mostly the 5H-isomer 7. Radial chromatography (sil-
ica gel, 2 mm rotor, 5% EtOAc/hexane) gave 126 mg of a mixture
of the two benzazepines, TLC Rf = 0.29. Radial chromatography
(silica gel, 1 mm rotor, 50% toluene/hexane) gave 50 mg of 5H-
benzazepine 7 (Rf = 0.30 in toluene; Rf of 2 = 0.39) as a yellow oil
1
Figure 3. H NMR spectra of 3H-benzazepine 11b at 10 °C (bot-
tom), –10 °C (middle) and –50 °C (top).
It is also important to compare and contrast the behavior
of 3H-benzazepine 2 with 5H-benzazepine 7. At room tem-
perature, the allylic protons appear as single resonances at
δ = 3.36 ppm and 3.55 ppm respectively for the 3H-benz-
azepine and 5H-benzazepine. Below –55 °C, the two allylic
protons of the 3H-benzazepine split into two signals at δ = which solidified when placed in a freezer for several days, m.p. 96–
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One-Flask Synthesis of 3H-1-Benzazepines
3
3
98 °C. Prolonged storage at low temperature in contact with glass
δ = 7.79 (d, JH,H = 8.3 Hz, 2 H), 7.42 (m, 2 H), 7.29 (t, JH,H
=
=
1
3
3
causes isomerization to 2. H NMR (400 MHz, CDCl3): δ = 8.08
7.5 Hz, 2 H), 7.23 (d, JH,H = 8.2 Hz, 2 H), 7.18 (tt, JH,H
7.4,1.2 Hz, 1 H), 4.93 (s, 1 H), 3.79 (d, JH,H = 17.3 Hz, 1 H), 3.26
3
3
3
(m, 2 H), 7.63 (dd, JH,H = 8.3,1.6 Hz, 2 H), 7.53 (d, JH,H
=
=
3
3
8.0 Hz, 1 H), 7.48 (m, 3 H), 7.38 (m, 4 H), 7.22 (tt, JH,H
(d, JH,H = 17.3 Hz, 1 H), 2.40 (s, 3 H), 1.84 (m, 2 H), 0.81 (t,
8.1,2.2 Hz, 2 H), 6.58 (s, 1 H), 3.55 (s, 2 H) ppm. 13C NMR
3JH,H = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.4,
(100 MHz, CDCl3): δ = 163.3, 149.0, 147.0, 140.3, 139.5, 131.0, 145.0, 144.7, 134.6, 129.4, 128.2, 128.1, 126.5, 125.0, 76.1, 47.1,
130.2, 128.8, 128.7, 128.5, 127.9, 127.2, 127.1, 127.0, 126.9, 126.3,
117.6, 36.4 ppm. HRMS calcd. for C22H17N + H m/z 296.1434,
found 296.1433.
36.1, 21.7, 7.8 ppm. HRMS calcd. for C18H20O2 + Na m/z
291.1356, found 291.1361.
(2E)-1-(4-Methylphenyl)-3-[4-(trifluoromethyl)phenyl]but-2-en-1-one
(9a): A solution of adol 8a (1.30 g, 4.03 mmol), triethylamine
3-Hydroxy-1-(4-methylphenyl)-3-[4-(trifluoromethyl)phenyl]butan-1-
one (8a): To a solution of TiCl4 (30 mL, 1.0  in CH2Cl2, 30 mmol) (2.41 mL, 17.3 mmol), and 4-(dimethylamino)pyridine (54 mg,
under N2 was added additional anhydrous CH2Cl2 (12 mL). The
resulting solution was cooled to 5 °C and a solution of 4Ј-(trifluoro-
methyl)acetophenone (5.6 g, 30 mmol) in anhydrous CH2Cl2
(10 mL) was added dropwise, giving a yellow precipitate. A solution
of the (trimethylsilyl)enol ether of 4Ј-methylacetophenone[6] (6.2 g,
30 mmol) in anhydrous CH2Cl2 (6 mL) was added dropwise, giving
a dark red cloudy mixture. This was warmed to room temp. and
held for 1 h. The crude mixture was poured into rapidly stirred ice
water (70 mL). The organic layer was removed, and the aqueous
0.44 mmol) in dry CH2Cl2 (6 mL) under N2, was cooled to 0–5 °C.
A solution of trifluoroacetic anyhydride (1.13 mL, 8.14 mmol) in
anhydrous CH2Cl2 (5 mL) was added dropwise. The resulting solu-
tion was warmed to room temp. and stirred for 22 h. The reaction
solution was poured into rapidly stirred saturated Na2CO3 (30 mL)
solution, and the resulting mixture was partitioned between H2O
(30 mL) and Et2O (30 mL). The organic layer was separated, and
the aqueous layer was extracted with Et2O (30 mL). The two or-
ganic layers were combined, and dried with MgSO4. Rotary evapo-
layer was extracted with CH2Cl2 (2ϫ15 mL). The three organic ration gave 3.13 g of yellow-orange solid. Purification by radial
layers were combined and washed with 5% NaHCO3 (2ϫ20 mL),
and once with brine (40 mL). The solution was dried with MgSO4
and suction filtered through a short pad of silica gel. Rotary evapo-
ration gave 8.4 g of viscous yellow liquid. Fractional recrystalli-
zation from hexane gave crops of 8a as white powder, totaling 3.4 g
(35% yield), m.p. 65–66 °C. 1H NMR (400 MHz, CDCl3): δ = 7.81
chromatography (silica gel, 8 mm rotor, 5% EtOAc/hexane) gave
882 mg (72% yield) of enone 9a as a yellow powder (Rf in 10%
EtOAc/hexane = 0.44). Analytically pure samples were obtained by
recrystallization from hexane, giving yellow crystalline powder,
1
3
m.p. 75–76 °C. H NMR (400 MHz, CDCl3): δ = 7.92 (dt, JH,H
=
3
8.2 & 1.7 Hz, 2 H), 7.69 (m, 4 H), 7.31 (d, JH,H = 8.2 Hz, 2 H),
3
3
3
3
(dt, JH,H = 8.3,1.9 Hz, 2 H), 7.60 (d, JH,H = 8.7 Hz, 2 H), 7.56
7.16 (q, JH,H = 1.3 Hz, 1 H), 2.58 (d, JH,H = 1.3 Hz, 3 H), 2.45
3
3
(d, JH,H = 8.7 Hz, 2 H), 7.26 (d, JH,H = 8.2 Hz, 2 H), 5.04 (s, 1
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.5, 152.5,
H), 3.78 (d, JH,H = 17.5 Hz, 1 H), 3.34 (d, JH,H = 17.5 Hz, 1 H), 146.4, 143.8, 136.3, 130.8 (q, 3JH,H = 32.8 Hz), 129.4, 128.5, 126.8,
3
3
2.42 (s, 3 H), 1.60 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
125.6 (q, JH,H = 3.7 Hz), 124.0 (q, JH,H = 272 Hz), 123.9, 21.7,
18.8 ppm. 19F NMR (377 MHz, CDCl3): δ = –63.3 ppm. HRMS
calcd. for C18H15F3O + H m/z 305.1148, found 305.1152.
3
3
= 200.7, 151.8, 145.1, 134.2, 129.5, 128.9 (q, 3JH,H = 33 Hz), 128.2,
3
3
125.3 (q, JH,H = 3.7 Hz), 124.9, 124.2 (q, JH,H = 272 Hz), 73.5,
48.2, 31.0, 21.7 ppm. 19F NMR (377 MHz, CDCl3): δ = –63.1 ppm.
HRMS calcd. for C18H17F3O2 + Na m/z 345.1073, found 345.1077.
(2E)-1-(4-Methylphenyl)-3-phenylpent-2-en-1-one (9b): The pro-
cedure as above, using aldol 8b, gave 31% yield of enone 9b as
a yellow viscous oil after chromatography, which solidified upon
standing, m.p. 48–50 °C. 1H NMR (400 MHz, CDCl3): δ = 7.89 (d,
3-Hydroxy-1-(4-methylphenyl)-3-phenylpentan-1-one (8b): The pro-
cedure as above using propiophenone gave 48% yield of aldol 8b
as white powder, m.p. 74–75 °C. 1H NMR (400 MHz, CDCl3): δ =
3
3JH,H = 8.2 Hz, 2 H), 7.53 (dd, JH,H = 7.6,2.0 Hz, 2 H), 7.40 (m,
7.79 (d, 3JH,H = 8.3 Hz, 2 H), 7.42 (m, 2 H), 7.29 (t, 3JH,H = 7.5 Hz, 3 H), 7.26 (d, JH,H = 8.2 Hz, 2 H), 7.02 (s, 1 H), 3.05 (q, JH,H
=
3
3
3
3
3
2 H), 7.23 (d, JH,H = 8.2 Hz, 2 H), 7.18 (tt, JH,H = 7.4,1.2 Hz, 1
7.5 Hz, 2 H), 2.41 (s, 3 H), 1.15 (t, JH,H = 7.5 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 191.3, 160.7, 143.3, 141.7, 136.7,
129.2, 128.9, 128.6, 128.5, 126.8, 122.1, 25.0, 21.6, 13.6 ppm.
HRMS calcd. for C18H18O + H m/z 251.1430, found 251.1434.
3
3
H), 4.93 (s, 1 H), 3.79 (d, JH,H = 17.3 Hz, 1 H), 3.26 (d, JH,H
=
3
17.3 Hz, 1 H), 2.40 (s, 3 H), 1.84 (m, 2 H), 0.81 (t, JH,H = 7.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.4, 145.0, 144.7,
134.6, 129.4, 128.2, 128.1, 126.5, 125.0, 76.1, 47.1, 36.1, 21.7, 7.8
ppm. HRMS calcd. for C18H20O2 + Na m/z 291.1356, found
291.1359.
2-Cyclohexylidene-1-(4-methylphenyl)ethanone (9c): The procedure
as above, using aldol 8c, with a four-day reaction time and using
50% toluene/hexane as chromatography eluent, gave 52% yield of
enone 9c as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.77
2-(1-Hydroxycyclohexyl)-1-(4-methylphenyl)ethanone (8c): The pro-
cedure as above using cyclohexanone gave 60% yield of aldol 8c as
white needles, m.p. 91–92 °C. 1H NMR (400 MHz, CDCl3): δ =
3
3
(d, JH,H = 8.1 Hz, 2 H), 7.16 (d, JH,H = 8.1 Hz, 2 H), 6.50 (s, 1
H), 2.68 (m, 2 H), 2.33 (s, 3 H), 2.23 (m, 2 H), 1.64 (m, 2 H), 1.56
(m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 192.2, 162.1,
143.1, 136.7, 129.1, 128.5, 118.8, 38.4, 30.7, 28.9, 28.0, 26.3, 21.6
3
3
7.85 (d, JH,H = 8.1 Hz, 2 H), 7.27 (d, JH,H = 8.1 Hz, 2 H), 4.07
(s, 1 H), 3.09 (s, 2 H), 2.42 (s, 3 H), 1.73 (m, 4 H), 1.61 (m, 1 H),
1.45 (m, 4 H), 1.28 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): ppm. HRMS calcd. for C15H18O + H m/z 215.1430, found
δ = 201.7, 144.5, 135.1, 129.4, 128.3, 71.0, 47.4, 37.8, 25.8, 22.0,
22.7 ppm. HRMS calcd. for C15H20O2 + Na m/z 255.1356, found
255.1360.
215.1427.
3-Methyl-1-(4-methylphenyl)but-2-en-1-one (9d):[20] Aldol 8d in the
crude reaction mixture spontaneously dehydrated to the enone 9d
upon standing for several days. Radial chromatography (silica gel,
15% EtOAc/hexane) gave enone 9d as a colorless oil, TLC Rf in
20% EtOAc/hexane = 0.45. Overall yield from acetone and the
(trimethylsilyl)enol ether of 4Ј-methylacetophenone = 35%.
3-Hydroxy-3-methyl-1-(4-methylphenyl)butan-1-one (8d): The pro-
cedure as above using acetone gave 63% crude yield of aldol 8d,
which was carried through to the next step without purification.
3-Hydroxy-2-methyl-3-(4-methylphenyl)-1-phenylbutan-1-one (8e):
The procedure as above using the (trimethylsilyl)enol ether of pro-
2-Methyl-3-(4-methylphenyl)-1-phenylbut-3-en-1-one (10): The pro-
cedure as above, using aldol 8e, and using 5% NaHCO3 rather than
piophenone, and 4Ј-methylacetophenone gave 48% yield of aldol
1
8e as white powder, m.p. 74–75 °C. H NMR (400 MHz, CDCl3): saturated Na2CO3 for the work-up, and 25% CH2Cl2/hexane for
Eur. J. Org. Chem. 2010, 2363–2371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2369

K. Ramig, E. M. Greer, et al.
FULL PAPER
the chromatography, gave 41% yield of enone 10 as a colorless oil
(TLC Rf in CH2Cl2 = 0.70) which solidified upon standing, m.p.
47–48 °C. The crude mixture also contained starting material which
0.647 mmol), 2-fluoroaniline (0.126 mL, 1.31 mmol) and pTsOH
(8 mg) in o-xylene (15 mL) was heated for 20 h under N2 in Dean–
Stark apparatus. After cooling, the solution was washed with 5%
NaHCO3 (15 mL) and dried with MgSO4. Rotary evaporation gave
199 mg of yellow viscous oil, which showed many components by
TLC with 50% CH2Cl2/hexane. Radial chromatography (silica gel,
1
could be purified and recycled. H NMR (400 MHz, CDCl3): δ =
3
3
7.93 (dd, JH,H = 7.2 & 1.4 Hz, 2 H), 7.52 (tt, JH,H = 7.4,1.4 Hz,
3
1 H), 7.40 (m, 4 H), 7.20 (d, JH,H = 7.9 Hz, 2 H), 5.41 (s, 1 H),
3
5.03 (s, 1 H), 4.57 (q, JH,H = 6.8 Hz, 1 H), 2.39 (s, 3 H), 1.51 (d,
1 mm rotor, 25% CH2Cl2/hexane) gave 65 mg (29% yield) imine 12
3JH,H = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.4, as a yellow oil, TLC Rf in 50% CH2Cl2/hexane = 0.45. H NMR
1
148.2, 137.8, 137.7, 136.4, 132.8, 129.3, 128.6, 128.5, 125.9, 114.1,
46.4, 21.1, 17.8 ppm. HRMS calcd. for C18H18O + Na m/z
273.1250, found 273.1252.
(400 MHz, CDCl3): δ = 8.01 (m, 2 H), 7.49 (m, 3 H), 7.09 (m, 5
H), 6.94 (m, 1 H), 6.86 (m, 2 H), 2.32 (s, 3 H), 1.81 (s, 3 H), 1.60
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5, 152.9 (d,
3
3JH,H = 247 Hz), 139.5 (d, JH,H = 12.7 Hz), 139.2, 137.0, 136.5,
2-(4-Methylphenyl)-4-[4-(trifluoromethyl)phenyl]-3H-1-benzazepine
(11a): A solution of enone 9a (523 mg, 1.72 mmol), 2-fluoroaniline
(0.250 mL, 2.59 mmol) and pTsOH monohydrate (20 mg) in o-xyl-
ene (25 mL) was heated at reflux under N2 for 19 h using Dean–
Stark apparatus. The solution was cooled to room temp., and
washed with 5% NaHCO3 (25 mL). Drying over MgSO4 and ro-
tary evaporation gave 605 mg of yellow solid. Trituration with
5 mL 2% EtOAc/hexane and suction filtration gave 362 mg (56%
yield) benzazepine 11a as a beige solid. Analytically pure samples
were obtained by dissolving in CH2Cl2 and passage of the solution
over a short silica gel column, and then recrystallization from 15%
EtOAc/hexane, giving light yellow crystalline powder, m.p. 155–
3
131.2, 129.0, 128.7, 128.5, 128.1, 127.6, 124.6 (d, JH,H = 7.4 Hz),
123.7 (d, 3JH,H = 3.8 Hz), 121.6 (d, 3JH,H = 2.3 Hz), 115.8 (d, 3JH,H
3
= 20.0 Hz), 23.4, 21.2, 19.0 (d, JH,H = 3.0 Hz) ppm. 19F NMR
(377 MHz, CDCl3): δ = –125.6 and –126.3 ppm, 6:1 area ratio,
respectively. HRMS calcd. for C24H22FN + H m/z 344.1809, found
344.1813. Presence of a 1:6 isomeric mixture is indicated by the 19
F
1
spectrum, and also by the H NMR spectrum. The latter showed
three small singlets at δ = 2.26, 1.94, and 1.91 ppm; these are attrib-
utable to the methyl groups of the minor isomer. The area all of
these together was 1/6 that of the three singlets at δ = 2.32, 1.81,
and 1.60 ppm, which are the methyl groups of the major isomer.
The 13C spectrum showed a minor set of resonances accompanying
all the peaks listed above.
1
3
156 °C. H NMR (400 MHz, CDCl3): δ = 7.82 (d, JH,H = 8.1 Hz,
3
3
2 H), 7.66 (s, 4 H), 7.62 (d, JH,H = 8.1 Hz, 1 H), 7.52 (d, JH,H
8.1 Hz, 1 H), 7.45 (td, JH,H = 7.6,1.5 Hz, 1 H), 7.27 (td, JH,H
=
=
3
3
2-Chloro-N-[(1E,Z)-(2E)-1,3-diphenylbut-2-en-1-ylidene]aniline (13):
3
A
solution of dypnone (1.00 g, 4.50 mmol), 2-chloroaniline
7.7,1.2 Hz, 1 H), 7.21 (d, JH,H = 8.1 Hz, 2 H), 7.15 (s, 1 H), 3.42
(s, 2 H), 2.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(0.492 mL, 4.68 mmol) and pTsOH (46 mg) in toluene (57 mL) was
heated at reflux under N2 in Dean–Stark apparatus for 16 h. After
cooling, the mixture was washed with 25 mL of 5% NaHCO3 and
dried with MgSO4. Rotary evaporation gave 1.12 g of crude prod-
3
157.1, 147.3, 143.4, 140.8, 135.1, 133.3, 130.6, 129.6 (q, JH,H
=
32.7 Hz), 129.4, 129.0, 128.5, 128.1, 128.0, 127.5, 127.0, 125.8 (q,
3
3JH,H = 3.6 Hz), 124.1 (q, JH,H = 272 Hz), 124.0, 33.5, 21.4 ppm.
1
19F NMR (377 MHz, CDCl3): δ = –63.1 ppm. HRMS calcd. for
C24H18F3N + H m/z378.1464, found 378.1469.
uct, which showed only imine 13 and dypnone by H NMR analy-
sis. Radial chromatography (silica gel, 4 mm rotor, 75% toluene/
hexane) gave 239 mg (16% yield) of imine 13 as a yellow oil. 1H
5-Methyl-2-(4-methylphenyl)-4-phenyl-3H-1-benzazepine (11b): The
procedure as above, using enone 9b and 2 equiv. 2-fluoroaniline,
and a six-hour reaction time, gave 53% yield of benzazepine 11b
as a yellow powder. Analytically pure samples and the sample for
X-ray analysis were obtained by recrystallization from 25% EtOAc/
3
NMR (500 MHz, CDCl3): δ = 7.93 (dd, JH,H = 8.4,1.4 Hz, 2 H),
3
7.39 (m, 3 H), 7.29 (dd, JH,H = 8.1,1.4 Hz, 1 H), 7.20 (m, 5 H),
3
3
7.10 (td, JH,H = 7.6,1.4 Hz, 1 H), 6.90 (td, JH,H = 7.7,1.5 Hz, 1
3
3
H), 6.81 (dd, JH,H = 7.8,1.3 Hz, 1 H), 6.28 (q, JH,H = 1.2 Hz, 1
H), 1.75 (d, JH,H = 1.2 Hz, 3 H) ppm. 13C NMR (126 MHz,
3
hexane, giving large yellowish hexagonal crystals, m.p. 140–143 °C.
3
1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 3 H), 7.52 (dd, JH,H
=
CDCl3): δ = 168.6, 148.7, 142.8, 141.5, 138.4, 131.1, 129.8, 128.7,
128.6, 128.4, 128.1, 127.0, 125.9, 124.6, 124.5, 122.5, 121.2, 19.0
ppm. HRMS calcd. for C22H18ClN + H m/z 332.1201, found
332.1196. Presence of a 1:11 isomeric mixture is indicated by peaks
in the 1H spectrum at δ = 6.05 ppm and 2.02 ppm; the former is
attributable to the vinylic proton, and the latter to the methyl
group, of the minor isomer. These two peaks individually had areas
1/11 that of the corresponding major-isomer peaks, the vinylic-pro-
ton quartet at δ = 6.28 ppm and the methyl-group doublet at δ =
1.75 ppm.
8.0,1.5 Hz, 1 H), 7.33 (m, 4 H), 7.23 (m, 1 H), 7.14 (m, 4 H), 3.96
(broad s, 1 H), 2.36 (broad s, 1 H), 2.34 (s, 3 H), 2.09 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 160.6, 147.2, 142.3, 140.4, 134.9,
133.8, 133.4, 130.2, 129.1, 128.8, 128.4, 128.1, 127.3, 127.2, 126.9,
126.6, 123.5, 37.1, 21.4, 18.7 ppm. HRMS calcd. for C24H21N + H
m/z 324.1747, found 324.1750.
6-(4-Methylphenyl)-8,9,10,11-tetrahydro-7H-dibenzo[b,d]azepine
(11c): The procedure was performed as above, using enone 9c at a
concentration of 0.04 , and a reaction time of 22 h. Purification
by radial chromatography (silica gel, 3% EtOAc/hexane) gave 54%
yield of benzazepine 11c as a yellow oil which solidified upon stor-
age in a freezer. Analytically pure samples were obtained by
recrystallization from hexane, giving yellowish pill-shaped solid,
CCDC-756838 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1
3
Supporting Information (see also footnote on the first page of this
article): Proton and carbon NMR spectra for all new compounds;
details on calculations including Cartesian coordinates absolute en-
ergies, ZPE, imaginary frequencies; additional crystallographic de-
tails including tables of structural data.
m.p. 87–88 °C. H NMR (400 MHz, CDCl3): δ = 8.00 (d, JH,H
=
=
3
3
8.3 Hz, 2 H), 7.62 (dd, JH,H = 7.9,1.5 Hz, 1 H), 7.51 (d, JH,H
3
8.2 Hz, 1 H), 7.32 (m, 3 H), 7.20 (dd, JH,H = 7.5,1.5 Hz, 1 H),
3.57 (broad s, 1 H), 2.87 (broad s, 1 H), 2.44 (s, 3 H), 2.28 (m, 4
H), 1.70 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.8,
146.8, 140.6, 135.1, 133.5, 131.3, 129.9, 129.3, 128.2, 127.2, 126.1,
125.9, 123.5, 35.9, 31.5, 28.0, 22.9, 22.8, 21.4 ppm. HRMS calcd.
for C21H21N + H m/z 288.1747, found 288.1751.
Acknowledgments
2-Fluoro-N-[(1E,Z)-(2E)-2-methyl-3-(4-methylphenyl)-1-phenylbut-
This work was supported in part by a grant from The City Univer-
sity of New York (PSC-CUNY Research Award Program). We
2-en-1-ylidene]aniline (12):
A solution of enone 10 (162 mg,
2370
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2363–2371

One-Flask Synthesis of 3H-1-Benzazepines
the C2–N1 single bond in 4 before cyclization can occur. The
same phenomenon can be seen in Scheme 8.
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thank Dr. Cliff Soll of the CUNY Mass Spectrometry Facility at
Hunter College for recording the high-resolution mass spectra. We
thank Dr. E. Fujita of Brookhaven National Laboratory for the
use of the CAD4 diffractometer for X-ray data collection. We
acknowledge the computational facility at the CUNY Graduate
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[11] J. Halfpenny, Acta Crystallogr., Sect. C 1992, 48, 1127–1129.
[12] See Supporting Information for details.
[13] The activation energy for proton transfer in anti-3 was found
to be prohibitively high, so the proton transfer must only occur
in the syn isomer as shown. This necessitates rotation around
[20] S. R. Krauss, S. G. Smith, J. Am. Chem. Soc. 1981, 103, 141–
148.
Received: December 15, 2009
Published Online: March 15, 2010
Eur. J. Org. Chem. 2010, 2363–2371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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