Regioselective alkylation reactions of 2,4-diphenyl-3H-1-benzazepine give either 3-alkyl-3H-1-benzazepines or 1-alkyl-1H-1-benzazepines

Article abstract of DOI:10.1016/j.tetlet.2014.05.128

2,4-Diphenyl-3H-1-benzazepine is deprotonated with either LDA or KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving either products of alkylation at C3, or at N, or a mixture of both. The regioselectivity depends on the base, presence of the complexing agent HMPA, and the leaving group of the alkylating agent. Using MeI as alkylating agent gives exclusively the C3-methylated product, while using MeOTs gives exclusively the N-methylated product. The N-alkylated products show evidence of stereodynamic behavior in their NMR spectra.

Full text of DOI:10.1016/j.tetlet.2014.05.128

Accepted Manuscript
Regioselective Alkylation Reactions of 2,4-Diphenyl-3H-1-benzazepine give
either 3-Alkyl-3H-1-benzazepines or 1-Alkyl-1H-1-benzazepines
Allen Ko, Aaron Lam, Jeffrey Li, Edyta M. Greer, David J. Szalda, Sasan
Karimi, Gopal Subramaniam, Keith Ramig
PII:
S0040-4039(14)00961-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.128
TETL 44719
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 May 2014
29 May 2014
30 May 2014
Please cite this article as: Ko, A., Lam, A., Li, J., Greer, E.M., Szalda, D.J., Karimi, S., Subramaniam, G., Ramig,
K., Regioselective Alkylation Reactions of 2,4-Diphenyl-3H-1-benzazepine give either 3-Alkyl-3H-1-benzazepines
or 1-Alkyl-1H-1-benzazepines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.128
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Ph
Me
N
Ph
N
Ph
Ph
Ph
N
KHMDS
Me
N
HMPA
Ph
Ph
Ph

Regioselective Alkylation Reactions of 2,4-Diphenyl-3H-1-benzazepine give
either 3-Alkyl-3H-1-benzazepines or 1-Alkyl-1H-1-benzazepines
Allen Ko,a Aaron Lam,a Jeffrey Li,a Edyta M. Greer,a David J. Szalda,a Sasan
Karimi,b Gopal Subramaniam,c Keith Ramig*,a
aDepartment of Natural Sciences, Baruch College of the City University of New
York, 17 Lexington Ave., New York, NY 10010, USA b Department of Chemistry,
Queensborough Community College of the City University of New York, 222-05
56th Ave., Bayside, NY 11364, USA cDepartment of Chemistry and Biochemistry,
Queens College of the City University of New York, 65-30 Kissena Blvd.,
Flushing, NY 11367, USA
*Corresponding author: keith.ramig@baruch.cuny.edu P: 1 646 660-6243
Abstract: 2,4-Diphenyl-3H-1-benzazepine is deprotonated with either LDA or
KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving
either products of alkylation at C3, or at N, or a mixture of both. The
regioselectivity depends on the base, presence of the complexing agent HMPA,
and the leaving group of the alkylating agent. Using MeI as alkylating agent gives
exclusively the C3-methylated product, while using MeOTs gives exclusively the
N-methylated product. The N-alkylated products show evidence of stereodynamic
behavior in their NMR spectra.
Keywords: 1-benzazepine, regioselective, alkylation, stereodynamic
INTRODUCTION
The stereodynamic properties of conformationally chiral nitrogen-atom-
containing medium-ring heterocycles, typified by 1-benzazepine derivatives, are a
subject of much current interest.1 The sense of conformational chirality can affect
the biological activity of these molecules. If the sense of conformational chirality
changes with time, this must be taken into account if the molecule is to be
developed into a drug.2,3 Placement of an alkyl group on the ring, which creates a
chiral center, can quicken or slow the rate of conformational exchange; more
importantly, this new chiral center can bias the conformational chirality and result

in preferential formation of a particular diastereomer.1,4-9 Thus, studies of the
effects of substitution are gaining importance in the development of new
heterocyclic drugs of this class.
We have reported a synthesis of 2-aryl-3H-1-benzazepines 1 which allows
placement of alkyl groups at C4 and C5 (Scheme 1).10 However, attempted
placement of a methyl group at C3 failed. To overcome this limitation, we
envisioned a deprotonation at C3 of a benzazepine, followed by an SN2-type
reaction with an akyl halide. Streef et al.11 have reported that 3H-azepines can be
deprotonated, and the resulting anion alkylated to give 3-alkyl-3H-azepines.
Similarly, we have reported that 2,4-diphenyl-3H-1-benzazepine (2) can be
deprotonated with LDA and the resulting anion alkylated with methyl iodide,
giving exclusively the 3-alkylated product, albeit in low yield.12 We report here
that the yield of this reaction can be improved, and the regioselectivity altered to
favor the novel N-alkylated isomers, by varying the base, complexing agent, and
the alkylating agent.
1 N
Ar
Ar
2
4
R1
R2
NH2
F
O
R1
R2
3
+
5
R3
R3
1
R1= Me
Scheme 1. Limitation in a synthesis of 2-arylbenzazepines.
RESULTS AND DISCUSSION
Treatment of benzazepine 213 with LDA or KHMDS, either with or without
the complexing agent HMPA, in THF at -72 °C, for either one hour (LDA) or 10
minutes (KHMDS), gives a deeply colored anion. To this solution is added an
alkyl halide, followed by warming to room temperature. Standard extractive
aqueous work-up and chromatographic purification gives the 3-alkylated products
3, and N-alkylated products 4 (Scheme 2).14 The 5-alkylated products were not
seen in any of the reactions. NMR yields were calculated based on the mass of
crude product, which contained the two alkylated products and sometimes starting
benzazepine.

1) LDA or
KHMDS,
THF
R
(HMPA)
-72 °C
Ph
R
Ph
Ph
Ph
Ph
N
N
N
+
2) RX
Ph
X = Cl, Br,
I, OTs
2
3
4
3a R=Me
3b R=Et
3c R=Bn
4a R=Me
4b R=Et
4c R=Bn
Scheme 2. Alkylation of benzazepine 2 to give 3-alkylated 3 and N-alkylated 4.
Table 1 shows the results of our attempts at methylation, ethylation, and
benzylation. Use of LDA as base and MeI as alkylating agent gave exclusively 3-
methyl 3a albeit in low yield (entry 1); use of excess MeI did not give an improved
yield. Use of excess KHMDS in place of LDA resulted in only recovered starting
material (entry 2); this surprising negative result was confirmed by repetition.
Inclusion of the complexing agent HMPA gave a mixture of 3-methyl 3a and N-
methyl 4a, favoring the former (entry 3). By the principles of HSAB theory,15 we
reasoned that use of the harder alkylating agent MeOTs may promote reaction at
the harder nitrogen atom of the deprotonated benzazepine. This proved to be the
case, as no 3-methyl 3a could be detected in the crude reaction mixture of entry 4.
As in methylation, the selectivity of the ethylation reactions (entries 5-8) showed
sensitivity to inclusion of HMPA (6 vs. 7), and choice of leaving group in the
alkylating agent (entry 7 vs 8).
The regioselectivity is also affected by the size of alkylating agent. As the
steric bulk of the alkyl halide increased, the selectivity for 3-alkylated 3 decreased
(compare entries 3 and 7). This effect was especially prominent in benzylation
reactions (entries 9-13) which showed the least regioselectivity. The first attempt
at benzylation (entry 9), using the conditions from entry 1, gave only stilbene, 2-
bromo-1,2-diphenylethane and recovered starting benzazepine; stilbene and 2-
bromo-1,2-diphenylethane are both products of base-induced self-condensation of
benzyl bromide. Use of KHMDS as base either without (entry 11) or with HMPA
present (entry 12) still resulted in a mixture of 3- and N-alkylated products. Unlike
the methylation and ethylation reactions, the selectivity of benzylation did not
change much with a change of leaving group in the alkyl halide (entry 12 vs. entry
13).

Finally, to maximize the yields, we used the system of Carlier et al.,16
consisting of 2.4 equivalents of KHMDS/HMPA. We found, as they did, that the
superstoichiometric amount of base is needed for acceptable yields.
Isolated yields
NMR yield
entry
1
base (eq.)
LDA (2.0)
eq. HMPA R-X (eq.)
(3:4)
3
31
0
4
0
0
MeI (1)
MeI (1)
MeI (5)
MeOTs (5)
EtI (1)
63 (100:0)
0 (-)
0
2
KHMDS (2.4)
KHMDS (2.4)
KHMDS (2.4)
LDA (2.4)
0
3
12
12
0
83 (89:11)
70 (0:100)
42 (90:10)
n.d. (80:20)
86 (68:32)
87 (30:70)
0 (-)
49
0
8
4
49
n.d.
n.d.
21
43
0
5
n.d.
n.d.
40
22
0
6
KHMDS (2.4)
KHMDS (2.4)
KHMDS (2.4)
LDA (2.0)
0
EtI (1)
7
12
12
0
EtI (1)
8
EtBr (1)
BnBr (4)
BnBr (1)
BnBr (1)
BnBr (1)
BnCl (1)
9
10
11
12
13
LDA (2.4)
12
0
n.d. (58:42)
83 (67:33)
98 (50:50)
95 (46:54)
n.d.
35
34
32
n.d.
13
33
33
KHMDS (2.4)
KHMDS (2.4)
KHMDS (2.4)
12
12
Table 1. Alkylation reactions of benzazepine 2, to go with Scheme 2.
The regioselectivity seen in the alkylation reactions can be explained in the
following way. After deprotonation by LDA, a resonance-stabilized anion such as
5 would be the result. The lithium ion may be more tightly bound to the nitrogen
atom. When an alkyl halide approaches, a cyclic transition state can be envisioned,
where the alkyl group of the alkyl halide will end up being attached to C3 because
of complexation of the lithium ion with the halogen atom. Thus, 3-alkylation is
favored. As the counterion is switched from lithium to potassium, and then to
potassium/HMPA, the anion becomes more and more naked. In this case, most of
the negative charge will reside on the N atom, causing it to be more nucleophilic
than C3. Especially in the presence of HMPA, the metal ion is not available to

orient the incoming alkyl halide, so N-alkylation is favored, or at least 3-alkylation
is slightly less favored. In either case, the alkyl group of the products 3 and 4 is
expected to be oriented in the axial sense, initially at least, based on
stereoelectronic considerations proposed in a closely related system.17
Li
X
R
H
R
Ph
Ph
Ph
Ph
N
N
Ph
N
-LiX
Ph
3
5
Scheme 3. Rationalization of C3-alkylation in anion 5 when lithium is the
counterion.
(a)
(b)

Figure 1. ORTEP diagrams of (a) N-methyl 4a, and (b) N-benzyl 4c. One
enantiomer of the two present in each compound is shown arbitrarily.
The regiochemical and stereochemical assignments were done by both X-ray
crystallography and 1H NMR analyses. The X-ray crystal structures of N-
alkylated 4a and 4c (Figure 1) show, in addition to puckered azepine rings,
considerably flattened nitrogen atoms which are out of the planes of their
respective benzo groups; in 4a the sum of the three C-N-C bond angles is 353°,
while the C19-C11-N-C7 dihedral angle is 30°.18 The alkyl groups of both are
oriented in the pseudoequatorial manner, although there is not much of a
distinction between axial and equatorial, as the hybridization of the nitrogen atom
must be close to sp2.
The 3-alkylated compounds 3b and 3c are solid, but crystals suitable for X-
ray analysis could not be obtained. Since the expected NMR spectra of the
possible 5-alkylated benzazepines would be similar to those of their 3-alkylated
isomers, a detailed NMR study was undertaken to confirm the proposed structures
of 3b and 3c. This was done by analyzing the coupling pattern, chemical shifts,
and NOE data. For example, doublets in the aromatic region of the proton
spectrum that integrate to two protons are markers for the ortho protons of the 2-
and 4- phenyl groups, while doublets that integrate to one proton each are assigned
to H6 and H9 of the benzazepines. This information when coupled with the
observed NOEs from H3 to the ortho protons of the 2- and 4- phenyl groups, and
also from H5 to H6, unequivocally confirmed the structures of 3b and 3c (see

supplementary data). The pseudoaxial orientation can be assigned to the alkyl
groups in these two based on similarities in their 1H NMR spectra when compared
to the 1H NMR spectra of 3-methyl 3a and benzazepine 2, which are well
characterized.12 In 3-methyl 3a, which is known to have its methyl group in the
pseudoaxial orientation,12 the chemical shift of the pseudoequatorial H3 is 5.00
ppm; the corresponding values for 3-ethyl 3b and 3-benzyl 3c match well, at 4.81
and 5.00 ppm, respectively. For comparison, the chemical shift of the
pseudoequatorial H3 in benzazepine 2 is 4.97 ppm, while the chemical shift of the
pseudoaxial H3 is much lower, at 1.98 ppm.10,19
The N-alkylated benzazepines provide an interesting contrast to their 3-
alkylated isomers. Both N-alkylated and 3-alkylated benzazepines contain two
elements of chirality, a chiral center and the conformationally chiral seven-
membered ring. A ring-flip, which inverts the seven-membered ring, converts 3-
methyl 3a to a diastereomer of the original structure, as the chiral center is not
inverted. In an earlier study,12 we found that 3-methyl 3a exists as the major
isomer (1,400:1) in equilibrium with its ring-flipped diastereomer, and that their
interconversion is fast (Gibbs free energy of activation (∆G‡) = 16.4 kcal/mol for
ring-flip of 3a) at room temperature. The situation may be much different for the
N-alkylated isomers 4a-c, as both chiral elements have the possibility of inverting.
Enantiomerization of the N-alkylated benzazepines would require both a ring-flip
of the azepine ring, and inversion of the N atom; these two processes could be
concomitant or occur independently of each other.
When a solution of N-benzyl 4c in CDCl3 is cooled below room temperature,
the singlet in the 1H NMR spectrum assigned to the diastereotopic benzylic
protons begins to broaden and eventually decoalesces at 278 K into a pair of
doublets. No other broadening of peaks is seen. This is an indication that a
dynamic stereochemical process is occurring, which is causing exchange between
the benzylic protons. Using the chemical shift difference (78.6 Hz) and the
geminal coupling constant (15.0 Hz), the ∆G‡ of the dynamic process at the
coalescence temperature can be calculated.20 For N-benzyl 4c, the ∆G‡ is found to
be 13.8 kcal/mol.
In conclusion, regioselective alkylation of a 3H-1-benzazepine provides access to
1-alkyl-1H-1-benzazepines, which present some very interesting stereochemical

features. The puckered azepine ring has planar chirality. Also, the nitrogen atom
in principle is a chiral center, although the X-ray crystal structure indicates
considerable deviation from pyramidal geometry towards trigonal planar.
Preliminary NMR evidence suggests that these molecules show dynamic
stereochemistry of some type. We plan a full computational and NMR
spectroscopic study that will allow assignment of free energy barriers to the
various stereodynamic processes that occur during enantiomerization of the N-
alkylated benzazepines. These processes include a ring-flip, inversion of the
nitrogen atom, rotations within the alkyl group, and rotation of the phenyl groups.
We expect our studies to add to the growing literature of medium-ring nitrogen-
atom-containing heterocycles, some important members of which exhibit planar
chirality and contain a chiral nitrogen atom.21-25
Supplementary data available: Experimental procedures for 3b, 3c, 4b, and 4c;
1H and 13C NMR spectra of 3b, 3c, and 4a-c; variable-temperature 1H NMR
spectra of 4b and 4c; NOE data for 3b and 3c; crystallographic data and
information about the data collection for 4a and 4c. Crystallographic data
(excluding structure factors) for 4a and 4c have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC
999481 (4a) and CCDC 999482 (4c). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44-(0)1223-336033 or e-mail:deposit@ccdc.cam.ac.Uk).
Acknowledgments
The Professional Staff Congress of the City University of New York is
acknowledged for financial support. We thank Olga Lavinda for helpful
discussions. We thank Dr. E. Fujita of Brookhaven National Laboratory for the
use of the Bruker Kappa Apex II diffractometer for X-ray data collection.
References and Notes

1)
2)
Ramig, K. Tetrahedron 2013, 69, 10783-10795.
Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem. Int.
Edit. 2009, 48, 6398-6401.
3)
LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O.
ChemMedChem 2011, 6, 505-513.
4)
5)
6)
Lam, P. C.-H.; Carlier, P. R. J. Org. Chem. 2005, 70, 1530-1538.
Pira, S. L.; Wallace, T. W.; Graham, J. P. Org. Lett. 2009, 11, 1663-1666.
Carlier, P. R.; Lam, P. C.-H.; DeGuzman, J. C.; Zhao, H. Tetrahedron-
Asymmetr. 2005, 16, 2998-3002.
7)
8)
Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004, 60, 4481-4490.
Ohnmacht, C. J.; Albert, J. S.; Bernstein, P. R.; Rumsey, W. L.; Masek, B.
B.; Dembofsky, B. T.; Koether, G. M.; Andisik, D. W.; Aharony, D.
Bioorg. Med. Chem. 2004, 14, 2653-2669.
9)
Tabata, H.; Suzuki, H.; Akiba, K.; Takahashi, H.; Natsugari, H. J. Org.
Chem. 2010, 75, 5984-5993.
10) Ramig, K.; Greer, E. M.; Szalda, D. J.; Razi, R.; Mahir, F.; Pokeza, N.;
Wong, W.; Kaplan, B.; Lam, J.; Mannan, A.; Missak, C.; Mai, D.;
Subramaniam, G.; Berkowitz, W. F.; Prasad, P.; Karimi, S.; Lo, N. H.;
Kudzma, L. V. Eur. J. Org. Chem. 2010, 2363-2371.
11) Streef, J. W.; van der Plas, H. C. Tetrahedron Letters 1979, 2287-2290.
12) Ramig, K.; Greer, E. M.; Szalda, D. J.; Karimi, S.; Ko, A.; Boulos, L.; Gu,
J.; Dvorkin, N.; Bhramdat, H.; Subramaniam, G. J. Org. Chem. 2013, 78,
8028-8036.
13) Kudzma, L. V. Synthesis 2003, 1661-1666.
14) Experimental procedures for 2,4-diphenyl-3-methyl-3H-1-benzazepine (3a)
and 2,4-diphenyl-1-methyl-1H-1-benzazepine (4a): To a solution of 2,4-
diphenyl-3H-1-benzazepine (2) (296 mg, 1.00 mmol) and HMPA (2.0 mL,
12 mmol) in 10 mL anhydrous THF at -72 °C under N2 was added dropwise
potassium hexamethyldisilazide (2.4 mL, 2.4 mmol; 1.0 M in THF), giving a
dark-brown solution. After 10 min, methyl iodide (0.310 mL, 4.98 mmol)
was added dropwise, and the color of the solution changed to red-orange.
The cold bath was removed, and after 25 min of warming to room
temperature, the solution changed to a milky yellow color. The solution was
partitioned between 8 mL H2O and 8 mL Et2O. The aqueous layer was
extracted with 2 x 8 mL Et2O, and the combined organic layer was washed

with 2 x 8 mL 1.0 M aqueous HCl. Drying of the organic layer over MgSO4
and rotary evaporation gave 271 mg crude product, which contained an
89:11 ratio of 3-methyl 3a:N-methyl 4a, as judged by relative 1H NMR peak
areas of the quartet at 5.00 ppm due to H3 in 3-methyl 3a, and the doublet at
5.84 ppm due to H3 in N-methyl 4a. Purification by radial chromatography
(silica gel, 1-mm rotor, 1% EtOAc/hexane) gave two fractions: N-methyl 4a
(25 mg, 8% yield) as an orange solid, mp = 101-103 °C, Rf = 0.50 in 5%
EtOAc/hexane; and 3-methyl 3a12 (152 mg, 49% yield). 2,4-diphenyl-1-
methyl-1H-1-benzazepine (4a): 1H NMR (500 MHz, CDCl3) δ 2.93 (s, 3H),
5.84 (d, J = 0.8 Hz, 1H), 6.94 (s, 1H), 7.01-7.05 (m, 2H), 7.09 (dd, J = 7.7,
1.9 Hz, 1H), 7.28-7.42 (m, 9H), 7.58 (dd, J = 8.4, 1.4 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 39.1, 118.0, 119.4, 123.5, 126.2 (2), 127.5, 127.7,
128.2 (4), 128.4 (2), 129.2, 129.9, 130.5, 134.8, 139.1, 141.1, 141.8, 152.8,
153.2; HRMS (CI) calcd. for C23H19N+H m/z 310.1590, found 310.1581.
Slow recrystallization from 10% EtOAc/hexane gave crystals of N-methyl
4a suitable for X-ray analysis. A crystal of N-methyl 4a was mounted on
the end of a glass fiber. Data collected at room temperature indicated
orthorhombic symmetry and systematic absences consistent with space
group Pbca. This space group was used for the solution and refinement of
the structure. Crystal data and information about the data collection are
provided in the supplementary data.
15) Smith, M. B. In March’s Advanced Organic Chemistry 7th ed.; John Wiley
& Sons, Inc.: Hoboken, NJ, USA, 2013; pp 331-334.
16) Carlier, P. R.; Zhao, H.; MacQuerrie-Hunter, S. L.; DeGuzman, J. C.; Hsu,
D. C. J. Am. Chem. Soc. 2006, 128, 15215-15220.
17) Carlier, P. R.; Sun, Y.-S.; Hsu, D. C.; Chen, Q.-H. J. Org. Chem. 2010, 75,
6588-6594.
18) The corresponding values for 4c are 353° and 34°.
19) The chemical shifts for the protons of the methylene group in benzazepine 2
aren’t strictly comparable to the chemical shifts of the H3 protons in the
others, as the solvents and temperatures are different. The two
diastereotopic methylene protons in benzazepine 2 are only distinguishable
at low temperature; at room temperature they appear together as a singlet
due to a fast ring-flip. Also, we have found the effect of solvent to be
minimal on the chemicals shifts of these types of protons.

20) Oki, M. Top. Stereochem. 1983, 14, 1-81.
21) Burke, E. W. D.; Morris, G. A.; Vincent, M. A.; Hillier, I. H.; Clayden, J.
Org. Biomol. Chem. 2012, 10, 716-719.
22) Liu, P.; Lanza Jr., T. J.; Chioda, M.; Jones, C.; Chobanian, H. R.; Guo, Y.;
Chang, L.; Kelly, T. M.; Kan, Y.; Palyha, O.; Guan, X.-M.; Marsh, D. J.;
Metzger, J. M.; Ramsay, K.; Wang, S.-P.; Strack, A. M.; Miller, R. J.; Pang,
J.; Lyons, K.; Dragovic, J.; Ning, J. G.; Schafer, W. A.; Welch, C. J.; Gong,
X.; Gao, Y.-D.; Hornak, V.; Ball, R. G.; Tsou, N.; Reitman, M. L.; Wyvratt,
M. J.; Nargund, R. P.; Lin, L. S. ACS Med. Chem. Lett. 2011, 2, 933-937.
23) Tabata, H.; Nakagomi, J.; Morizono, D.; Oshitari, T.; Takahashi, H.;
Natsugari, H. Angew. Chem. Int. Edit. 2011, 50, 3075-3079.
24) Tabata, H.; Wada, N.; Takada, Y.; Nakagomi, J.; Tomohiro, M.; Shirahase,
H.; Oshitari, T.; Takahashi, H.; Natsugari, H. Chem.-Eur. J. 2012, 18, 1572-
1576.
25) Hasan, M.; Nizami, T. A.; Malik, A.; Ohlendorf, C.; Hiller, W.; Voelter, W.
Z. Naturforsch. 1998, 53b, 485-487.
Table 1. Alkylation reactions of benzazepine 2, to go with Scheme 2.
Figure 1. ORTEP diagrams of (a) N-methyl 4a, and (b) N-benzyl 4c. One
enantiomer of the two present in each compound is shown arbitrarily.
Scheme 1. Limitation in a synthesis of 2-arylbenzazepines.
Scheme 2. Alkylation of benzazepine 2 to give C-alkylated 3 and N-alkylated 4.
Scheme 3. Rationalization of C3-alkylation in anion 5 when lithium is the
counterion.

1 N
Ar
Ar
2
4
R1
R2
NH2
F
O
R1
R2
3
+
5
R3
R3
1
R1= Me

1) LDA or
KHMDS,
THF
R
(HMPA)
-72 °C
Ph
R
Ph
Ph
Ph
Ph
N
N
N
+
2) RX
X = Cl, Br,
I, OTs
Ph
2
3
4
3a R=Me
3b R=Et
3c R=Bn
4a R=Me
4b R=Et
4c R=Bn

Li
X
R
H
R
Ph
Ph
Ph
Ph
N
N
Ph
N
-LiX
Ph
3
5

Isolated yields
entry base (eq.)
eq. HMPA R-X (eq.) NMR yield (3:4)
3
4
1
LDA (2.0)
0
MeI (1)
MeI (1)
MeI (5)
63 (100:0)
0 (-)
31
0
0
2
KHMDS (2.4) 0
KHMDS (2.4) 12
KHMDS (2.4) 12
0
3
83 (89:11)
49
0
8
4
MeOTs (5) 70 (0:100)
49
n.d.
n.d.
21
43
0
5
LDA (2.4)
0
EtI (1)
42 (90:10)
n.d. (80:20)
86 (68:32)
87 (30:70)
0 (-)
n.d.
n.d.
40
22
0
6
KHMDS (2.4) 0
KHMDS (2.4) 12
KHMDS (2.4) 12
EtI (1)
7
EtI (1)
8
EtBr (1)
BnBr (4)
BnBr (1)
BnBr (1)
BnBr (1)
BnCl (1)
9
LDA (2.0)
LDA (2.4)
0
10
11
12
13
12
n.d. (58:42)
83 (67:33)
98 (50:50)
95 (46:54)
n.d.
35
34
32
n.d.
13
33
33
KHMDS (2.4) 0
KHMDS (2.4) 12
KHMDS (2.4) 12

Graphical abstract
Ph
Me
N
Ph
N
Ph
Ph
Ph
N
KHMDS
HMPA
Me
Ph
Ph
N
Ph