Simple and efficient methods of synthesis of 3,3-diarylcyclobutanone and 3,3-diarylcyclobutylamine derivatives using the TiCl4/R3N reagent system

Article abstract of DOI:10.1021/jo0504215

The iminium ions generated in situ by the oxidation of N,N-diisopropyl-N- benzylamine using iodine react with diaryl ketones in the presence of TiCl ₄/R₃N to give the corresponding 3,3-diarylcyclobutanones in moderate to good yields

Full text of DOI:10.1021/jo0504215

Simple and Efficient Methods of Synthesis of
3,3-Diarylcyclobutanone and 3,3-Diarylcyclobutylamine
Derivatives Using the TiCl4/R3N Reagent System
Mariappan Periasamy,* K. Natarajan Jayakumar, and Pandi Bharathi
School of Chemistry, University of Hyderabad, Central University P. O., Hyderabad-500 046, India
mpsc@uohyd.ernet.in
Received March 5, 2005
The iminium ions generated in situ by the oxidation of N,N-diisopropyl-N-benzylamine using iodine
react with diaryl ketones in the presence of TiCl4/R3N to give the corresponding 3,3-diarylcyclo-
butanones in moderate to good yields (49-86%). The 3,3-diarylcyclobutanone iminium ions formed
in this transformation was reduced in situ with B2H6 to produce the corresponding 3,3-
diarylcyclobutylamines (52-79% yields), a class of compounds with potential antidepressant activity.
In addition, a series of N,N-dimethyl-3,3-diarylcyclobutylamines were synthesized by the reductive
amination of the corresponding 3,3-diarylcyclobutanone derivatives.
Introduction
available starting materials such as diaryl ketones should
be useful. Previously, synthesis of such cyclobutanone
derivatives have been reported via methods such as the
2 + 2 cycloaddition of ketenes to olefins,4 ring enlarge-
ment of cyclopropanones formed by addition of diazo-
methane to ketenes,5 the 2 + 2 cycloaddition of dichlo-
roketene to olefins,6 the 2 + 2 cycloaddition of keten-
iminium salts to olefins,7 and the condensation of alde-
hydes and ketones with diphenylsulfonium cyclopropylide
followed by acid treatment.8 Recently, a review covering
methods of synthesis of cyclobutanones and their precur-
sors has been published.9 Herein, we describe the syn-
theses of 3,3-diarylcyclobutanone and 3,3-diarylcyclo-
butylamine derivatives by the TiCl4/R3N-promoted reac-
tion of iminium ions with diaryl ketones.
Several functionalized cyclobutane derivatives have
been shown to possess significant biological activity.1 For
example, certain 3,3-diphenylcyclobutylamine derivatives
exhibit antidepressant activity.2 Accordingly, the corre-
sponding synthons containing cyclobutyl moieties are
useful intermediates for the construction of a wide variety
of biologically active carbocyclic compounds.3 Hence,
development of a simple and efficient methodology for
the synthesis of these functionalized cyclobutyl (cyclo-
butanones and cyclobutylamines) derivatives from readily
(1) (a) Cyclobut-A and related antiviral compounds: Norbeck, D. W.;
Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham, H.; Herrin, T.; Plattner,
J. J.; Erisckson, J.; Clement, J.; Swanson, R.; Shipkowitz, N.; Hardy,
D.; Marsh, K.; Arnett, G.; Shannon W.; Broder, S.; Mitsuya, H. J. Med.
Chem. 1990, 33, 1281. (b) Brown, B.; Hegedus, L. S. J. Org. Chem.
1998, 63, 8012 and references cited therein. (c) Friesen, R. W.; Dube,
D.; Fortin, R.; Frenette, R.; Prescott, S.; Cromlish, W.; Greig, G. M.;
Kargman, S.; Wong, E.; Chan, C. C.; Gordon, R.; Xu, L. J.; Rideneau,
D. Bioorg. Med. Chem. Lett. 1996, 6, 2677. (d) Delincee, H.; PoolZobel,
B. L. Radiat. Phys. Chem. 1998, 52, 39.
Results and Discussion
Synthesis of Cyclobutanone Derivatives via 1,3-
Dimetalation of Iminium Ions with TiCl4/R3N Re-
(2) Carnmalm, B.; Ramsby, S.; Renyi, A. L.; Ross, S. B.; Ogren, S.-
O.; Stjernstrom, N. E. J. Med. Chem. 1978, 21, 78.
(4) Marvel, C. S.; Kohan, M. I. J. Org. Chem. 1951, 16, 741.
(5) Michejda, C. J.; Comnick, R. W. J. Org. Chem. 1975, 40, 1046.
(6) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879.
(7) Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. Angew. Chem.,
Int. Ed. Engl. 1974, 13, 267.
(8) Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973, 95,
5321 and references cited there in.
(9) Salaun, J. Scie. Synth. 2004, 26, 557.
(3) (a) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27,
797. (b) Nemoto, H.; Fukumoto, K. Synlett 1997, 863. (c) Adam, J. M.;
Ghosez, L.; Houk, K. N. Angew. Chem., Int. Ed. 1999, 38, 2728. (d)
Brown, R. C. D.; Hinks, J. D. J. Chem. Soc., Chem. Commun. 1998,
1895. (e) Lee-Ruff, E.; Ostrowski, M.; Ladha, A.; Stynes, D. V.; Vernik,
I.; Jiang, J. L.; Wan, W. Q.; Ding, S. F.; Joshi, S. J. Med. Chem. 1996,
39, 5276.
10.1021/jo0504215 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/08/2005
5420
J. Org. Chem. 2005, 70, 5420-5425

3,3-Diarylcyclobutanone and 3,3-Diarylcyclobutylamine Derivatives
SCHEME 1. Synthesis of r,â-Unsaturated
Aldehydes
SCHEME 3. One-Pot Synthesis of
3,3-Diarylcyclobutanone Derivatives
SCHEME 2. Reaction of
N,N-Diisopropyl-N-octylamine with TiCl4/PhCOPh
Previously, it was reported that the iminium ions and
enamines are generated from the oxidation of tertiary
amines by iodine.12 The iminium ion prepared from the
oxidation of N,N-diisopropyl-N-methylamine by iodine
was reacted with TiCl4/N,N-diisopropyl-N-methylamine/
benzophenone. However, the corresponding cyclobu-
tanone derivative was obtained only in very low yield
(4%). The use of other tertiary amines such as N-
isopropylpiperidine and N,N-dimethyl-N-isopropylamine
for the preparation of iminium ions using iodine, followed
by the reaction with TiCl4/corresponding tertiary amine/
benzophenone did not give the expected cyclobutanone
derivative. Fortunately, in the reaction of iminium ions
with TiCl4/N,N-diisopropyl-N-benzylamine and benzo-
phenone the corresponding cyclobutanone derivative was
obtained in 76% yield (Scheme 3).
This transformation was examined using several diaryl
ketones, and the results are summarized in Table 1. We
have carried out several experiments to examine the
scope and limitations of this transformation. Initially, the
reaction was carried out at 25 °C after the addition of
TiCl4 to the iminium ions at 0 °C. It was found that the
yields of cyclobutanone are slightly better (10-20% more)
under refluxing conditions. Dichloroethane was found to
be the best solvent compared to CH2Cl2 and CHCl3 under
these reaction conditions. The yields are optimum when
2 equiv of tertiary amine was oxidized using 1 equiv of
iodine and the iminium iodide was reacted with 3 equiv
of TiCl4 and tertiary amine and 1 equiv of the diaryl
ketone. It was found that the second addition of tertiary
amine is needed for the reaction of the iminium ions
without which the cyclobutanone was not formed. The
use of TMEDA instead of N,N-diisopropyl-N-benzylamine
for the reaction of the iminium ion gave the cyclo-
butanone derivative in poor yields (6%).
It was reported that in the presence of excess trialkyl-
amine the iodine oxidation of trialkylamine produces
enamines.12 To examine whether such enamine interme-
diates could react with diaryl ketone to produce the
corresponding cyclobutanone derivatives, we have carried
out experiments without using TiCl4. However, the
cyclobutanone derivative was not formed in the absence
of TiCl4.
agent System.10 It has been previously reported from
this laboratory that the iminium ions formed in situ by
the reaction of trialkylamines by TiCl4 readily react with
diaryl ketones to give the corresponding R,â-unsaturated
aldehydes (Scheme 1).11
It was of interest to examine the reaction of the
iminium ions produced in situ using N,N-diisopropyl-N-
ethylamine (eq 1).
Interestingly, in this case, the product mixture showed
the presence of a cyclobutanone derivative 3 (IR 1790
cm-1) besides the corresponding R,â-unsaturated alde-
hyde. However, the product mixture was obtained only
in very small amounts. The use of N,N-diisopropyl-N-
octylamine produced the product mixture from which the
corresponding cyclobutanol 4 could be readily separated
after reduction of the product mixture of 2 and 3 with
NaBH4-MeOH-H2O (overall yield 12%) (Scheme 2).
Efforts undertaken to optimize the reaction conditions
using other amines such as N,N-diisopropyl-N-meth-
ylamine also gave poor results. Therefore, we have
examined the use of iminium ions prepared using other
methods in the reaction with TiCl4/PhCOPh/R3N.
To examine the generality of this methodology, the
reaction of iminium ion intermediate I was carried out
(10) Periasamy, M.; Jayakumar, K. N.; Bharathi, P. Chem. Commun.
2001, 1728.
(11) Bharathi, P.; Periasamy, M. Org. Lett. 1999, 1, 857.
(12) Wadsworth, D. H.; Detty, M. R.; Murray, B. J.; Weidner, C. H.;
Haley, N. F. J. Org. Chem. 1984, 49, 2676 and references therein.
J. Org. Chem, Vol. 70, No. 14, 2005 5421

Periasamy et al.
TABLE 1. Reaction of Iminium Ions with TiCl4/R3N and
Diaryl Ketones
SCHEME 5. Tentative Mechanistic Pathway for
the Formation of 3,3-Diarylcyclobutanone
Derivatives
TiCl4/N,N-diisopropyl-N-benzylamine could give the 1,3-
dititanated iminium ion intermediate IV via the inter-
mediacy of III (Scheme 5, path A). The reaction of the
species IV with diaryl ketone could give the correspond-
ing cyclobutanone derivative. However, the possibility of
an alternative mechanism involving sequential metala-
tion-addition reactions via the intermediates III, V, and
VI cannot be ruled out (Scheme 5, path B).
a The products were identified by 1H and 13C NMR and mass
spectral data. b The yields are based on the diaryl ketone used.
SCHEME 4. Reaction of Acetophenone with
Iminium Ion I/TiCl4/i-Pr2NBn
There are two possibilities for the iminium ion forma-
tion. It can form either at the isopropyl moiety or at the
benzylic moiety. Since benzaldehyde was not isolated and
the corresponding cyclobutanone was isolated as a major
product in this reaction, the major pathway is the
formation of iminium ion via deprotonation of the iso-
propyl group (Scheme 6).
Though the mechanistic path way involved is not
clearly understood at this stage, the one-pot method of
conversion of diaryl ketones to 3,3-diarylcyclobutanone
derivatives described here may serve as a simple alterna-
tive procedure to hitherto known methods of synthesis
of cyclobutanone derivatives.4-9
Synthesis of 3,3-Diarylcyclobutylamines by the
Reduction of 3,3-Diarylcyclobutanone Iminium Ions
by B2H6. It was reported that certain 3,3-diphenylcy-
clobutylamines are potential antidepressant agents.2
These compounds strongly decrease the accumulation of
noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in
brain slices in vitro and in vivo. It occurred to us that
the reduction of the intermediate iminium ion (Scheme
7) in situ would lead to the corresponding cyclobut-
ylamine derivatives. Indeed, we observed that when 3,3-
with TiCl4/N,N-diisopropyl-N-benzylamine/arylalkyl ke-
tones or dialkyl ketones. The reaction of acetophenone
with I/TiCl4/N,N-diisopropyl-N-benzylamine gave a com-
plex mixture of products in addition to the triple self-
condensation product of acetophenone, 1,3,5-triphenyl-
benzene 13 in 16% yield (Scheme 4). Recently, it has been
reported that such triple self-condensation of ketones is
promoted by titanium tetrachloride13 and also by TiCl3-
(OTf).14 An unidentifiable mixture of products was ob-
tained when the reaction was carried out using diethyl
ketone.
The tentative mechanistic pathway for the formation
of cyclobutanone derivative is described in Scheme 5.
Reaction of 2 equiv of tertiary amine and 1 equiv of iodine
would give the iminium iodide I.12 Further reaction with
(13) Li, Z.; Sun, W.-H.; Jin, X.; Shao, C. Synlett 2001, 1947.
(14) Iranpoor, N.; Zeynizaded, B. Synlett 1998, 1079.
5422 J. Org. Chem., Vol. 70, No. 14, 2005

3,3-Diarylcyclobutanone and 3,3-Diarylcyclobutylamine Derivatives
TABLE 2. Reduction of 3,3-Diarylcyclobutanone
SCHEME 6. Two Possibilities of Formation of
Iminium Ions from
N,N-Diisopropyl-N-benzylamine and Iodine
Iminium Ions with B2H6
SCHEME 7. One-Pot Synthesis of
3,3-Diarylcyclobutylamine Derivatives
diarylcyclobutanone iminium salt prepared in situ is
readily reduced with B2H6, generated using NaBH4/I2
reagent system,15 to the corresponding 3,3-diarylcyclo-
butylamines in moderate to good yields (Scheme 7, Table
2). The reaction of symmetrical diaryl ketones produced
the corresponding cyclobutylamines in moderate to good
yields (entries 1-5). When an unsymmetrical diaryl
ketone, 4-methylbenzophenone, was used, a mixture of
isomers 19 was obtained in 69% yield. The reaction of
1,4-dibenzoylbenzene produced 20 as a mixture of iso-
mers in 52% yield. Efforts to prepare iminium ions using
the tertiary amines N,N-dimethyl-N-isopropylamine, N-
isopropylpiperidine, and N,N-diisopropyl-N-methylamine
and iodine were not successful. The formation of 3,3-
diarylcyclobutylamine derivatives presented here also
illustrates the intermediacy of 3,3-diarylcyclobutanone
iminium ions in the reaction using TiCl4/tertiary amines
with diaryl ketones.
a The products were identified by 1H and 13C NMR and mass
spectral data. b The yields are based on the diaryl ketone used.
SCHEME 8. Synthesis of
N,N-Dimethyl-3,3-diarylcyclobutylamines
N,N-Dimethyl-3,3-diphenylcyclobutylamine is the most
potent compound known to cause motor stimulation.2
Therefore, it was of interest to synthesize such com-
pounds by reductive amination of the readily accessible
cyclobutanone derivatives. When 3,3-diarylcyclobutanone
derivatives were treated with dimethylammonium for-
mate,2 the corresponding N,N-dimethylcyclobutylamine
derivatives were obtained in 69-82% yields (Scheme 8).
This method compares favorably with the multistep
syntheses (∼10% overall yield) of such compounds fol-
lowing methods reported previously.2
Conclusions
A simple method of conversion of diaryl ketones to 3,3-
diarylcyclobutanones using readily available starting
materials has been developed. Convenient method of
synthesis of 3,3-diarylcyclobutylamines, a system with
promising biological activity, has been developed. A series
of N,N-dimethyl-3,3-diarylcyclobutylamines have been
synthesized by the reductive amination of the corre-
sponding 3,3-diarylcyclobutanone derivatives. The avail-
ability of simple and efficient methods of synthesis of the
cyclobutylamine system with potential biological activity
should stimulate further research activities in this area.
(15) Periasamy, M.; Narayana, C. J. Organomet. Chem. 1987, 323,
145.
J. Org. Chem, Vol. 70, No. 14, 2005 5423

Periasamy et al.
first eluted using hexane, and then 1,3,5-triphenylbenzene 13
was eluted next (0.12 g, 16%). 13: mp 172-174 °C (lit.11 mp
172 °C); 13C NMR δ 142.43, 141.25, 128.90, 127.59, 127.42,
125.53; 1H NMR δ 7.80 (s, 3H), 7.75-7.30 (m, 15H); EI/MS
m/z (r.i.) 306 (M+, 100).
Experimental section
Representative Procedure for the Preparation of 3,3-
Diarylcyclobutanone Derivatives (5). Iodine (0.63 g, 2.5
mmol) and N,N-diisopropyl-N-benzylamine (0.96 g, 5 mmol)
were taken in dichloroethane (40 mL) under N2, and the
mixture was refluxed at 95-100 °C for 2 h and brought to 25
°C under N2. Benzophenone (0.46 g, 2.5 mmol) dissolved in 5
mL of dichloroethane was added, and TiCl4 (1.65 mL of 1:1
solution of TiCl4-CH2Cl2, 7.5 mmol) was added at 0 °C
followed by N,N-diisopropyl-N-benzylamine (1.43 g, 7.5 mmol).
The contents were stirred at 0 °C for 10 min and then refluxed
at 95-100 °C for 6 h. The contents were brought to rt, and
then a saturated NH4Cl solution (20 mL) was added and the
resulting mixture stirred for 0.5 h. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(2 × 25 mL). The combined organic extract was washed with
5 N HCl (2 × 20 mL) to remove the unreacted amine, followed
by water and brine solution (10 mL), and dried over anhydrous
MgSO4. The solvent was removed, and the residue was
chromatographed on a silica gel column. Unidentified less
polar compounds and the unreacted ketone were eluted using
1:99 EtOAc/hexane mixture. The 3,3-diphenylcyclobutanone
5 was eluted using 2:98 EtOAc/hexane (0.26 g, 76%). 5: mp
83-84 °C (lit.16 mp 84-85 °C); IR (cm-1) νCdO 1786; 13C NMR
δ 205.2, 147.2, 128.7, 126.8, 126.5, 60.5, 42.0; 1H NMR δ 7.40-
7.20 (m, 10H), 3.80 (s, 4H). 6: mp 110-112 °C; IR (cm-1) νCdO
1790, 1770; 13C NMR δ 203.7, 145.2, 132.7, 128.9, 128.0, 60.4,
Representative Procedure for the Synthesis of 3,3-
Diarylcyclobutylamine Derivatives. Iodine(0.63 g, 2.5
mmol) and N,N-diisopropyl-N-benzylamine (0.96 g, 5 mmol)
were taken in dichloroethane (40 mL) under N2, and the
mixture was refluxed at 95-100 °C for 2 h and brought to 25
°C under N2. Benzophenone (0.46 g, 2.5 mmol) dissolved in 5
mL of dichloroethane was added, and TiCl4 (1.65 mL of 1:1
solution of TiCl4-CH2Cl2, 7.5 mmol) was added at 0 °C
followed by N,N-diisopropyl-N-benzylamine (1.43 g, 7.5 mmol).
The contents were stirred at 0 °C for 10 min and then refluxed
at 95-100 °C for 6 h. The contents were brought to rt, and
the diborane, generated using a solution of iodine (2.52 g, 10
mmol) in diglyme (10 mL) and NaBH4 (0.76 g, 20 mmol) in
diglyme (10 mL), was bubbled through the solution at 0 °C
for a period of 2 h. The outlet from the flask was vented
through a mercury bubbler and a trap containing adequate
amount of acetone to destroy excess diborane. When the
bubbling of the gases in the reaction flask had ceased, the
bubbler was removed under nitrogen and replaced by a glass
stopper. The reaction was continued for a further period of 3
h at 25 °C. A saturated K2CO3 solution (20 mL) was added
and stirred for 0.5 h. The reaction mixture was filtered through
a Buchner funnel. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic extract was washed with brine solution (10
mL) and dried over anhydrous K2CO3. The solvent was
removed. The unreacted N,N-diisopropyl-N-benzylamine was
distilled out under reduced pressure, bp 116-118 °C/34 mm
(lit.17 bp 118-120 °C/34 mm). The recovered N,N-diisopropyl-
N-benzylamine can be used again for these reactions by
redistilling it over CaH2. The residue was chromatographed
on a neutral alumina column. A small amount of unreacted
N,N-diisopropyl-N-benzylamine was first eluted using
0.25:99.75 EtOAc-hexane mixture. The N-benzyl-N-isopropyl-
3,3-diphenylcyclobutylamine was next eluted (0.65 g, 73%).
14: mp 38-40 °C; 13C NMR δ 151.2, 148.0, 142.4, 128.5, 128.3,
128.1, 126.9, 126.5, 125.9, 125.7, 125.4, 51.4, 50.7, 49.4, 45.2,
42.0, 18.9; 1H NMR δ 7.64-7.16 (m, 15H), 3.70 (s, 2H), 3.64-
3.44 (m, 1H) 3.24-2.96 (m, 3H), 2.80-2.60 (m, 2H), 1.12 (d, J
) 6.84 Hz, 6H); EI/MS m/z (r.i.) 355 (M+, 3), 264 (14), 175 (80),
91 (100). 15: mp 94-96 °C; 13C NMR δ 148.9, 145.9, 142.0,
131.7, 131.4, 128.6, 128.5, 128.2, 128.1, 127.1, 126.5, 51.1, 50.5,
1
41.3; H NMR δ 7.32-7.20 (m, 8H), 3.77 (s, 4H); EI/MS m/z
(r.i.) 294 [(M+ - 1) + 4, 1], 292 [(M+ - 1) + 2, 7], 290 [(M+
-
1), 11], 248 (100), 178 (94). 7: mp 71-73 °C; IR (cm-1) νCdO
1786; 13C NMR δ 205.6, 144.6, 136.0, 129.3, 126.6, 60.5, 41.4,
20.9; 1H NMR δ 7.30-7.18 (m, 8H), 3.80 (s, 4H), 2.40 (s, 6H);
EI/MS m/z (r.i.) 250 (M+, 36), 235 (72), 208 (100), 193 (99). 8:
mp 114-116 °C; IR (cm-1) νCdO 1790, 1774; 13C NMR δ 203.8,
163.9, 159.0, 142.8, 128.3, 115.8, 115.3, 60.7, 41.1; 1H NMR δ
7.30-6.96 (m, 8H), 3.76 (s, 4H). Anal. Calcd for C16H12F2O:
C, 74.41; H, 4.68; F, 14.71; O, 6.20. Found: C, 74.51; H, 4.61.
9: mp 64-65 °C; IR (cm-1) νCdO 1790; 13C NMR δ 205.2, 147.5,
144.3, 136.1, 129.4, 128.7, 126.7, 126.5, 60.5, 41.7, 20.9; 1H
NMR δ 7.40-7.20 (m, 9H), 3.85 (s, 4H), 2.40 (s, 3H); EI/MS
m/z (r.i.) 236 (M+, 38), 221 (40), 194 (94), 179 (100). 10: mp
145-147 °C; IR (cm-1) νCdO 1786; 13C NMR δ 205.6, 150.0,
140.1, 128.0, 127.8, 121.8, 120.1, 58.9, 41.4; 1H NMR δ 7.80-
7.35 (m, 8H), 3.66 (s, 4H); EI/MS m/z (r.i.) 220 (M+, 15), 178
(100). 11: mp 153-155 °C; IR (cm-1) νCdO 1784, 1768; 13C NMR
δ 207.4, 147.3, 128.3, 126.6, 126.4, 98.4, 68.7, 68.3, 66.6, 61.4,
37.0; 1H NMR δ 7.4-7.2 (m, 5H), 4.2 (s, 9H), 4.0-3.7 (m, 4H);
EI/MS m/z (r.i.) 330 (M+, 54), 288 (100). 12: mp 218-220 °C;
IR (cm-1) νCdO 1786, 1766; 13C NMR δ 204.9, 146.9, 145.4,
128.7, 126.9, 126.7, 126.6, 60.4, 41.6; 1H NMR δ 7.40-7.20 (m,
14H), 3.78 (s, 8H). Anal. Calcd for C26H22O2: C, 85.22; H, 6.05;
O, 8.73. Found: C, 85.31; H, 5.98.
1
49.3, 44.3, 41.8, 18.7; H NMR δ 7.44-6.96 (m, 13H), 3.56 (s,
2H), 3.48-3.28 (m, 1H), 3.01 (quintet, J ) 6.84 Hz, 1H), 2.88-
2.72 (m, 2H), 2.56-2.40 (m, 2H), 1.00 (d, J ) 6.84 Hz, 6H);
EI/MS m/z (r.i.) 424 (M+, 2), 298 (7), 174 (71), 91 (100). Anal.
Calcd for C26H27Cl2N: C, 73.58; H, 6.41; Cl, 16.71; N, 3.30.
Found: C, 73.65; H, 6.39; N, 3.32. 16: 13C NMR δ 163.5, 163.3,
158.7, 158.5, 146.7, 143.4, 142.2, 128.4, 128.2, 128.0, 127.4,
127.2, 126.4, 115.4, 115.2, 115.0, 114.8, 51.1, 50.6, 49.3, 44.1,
42.1, 18.7; 1H NMR δ 7.48-6.88 (m, 13H), 3.61 (s, 2H), 3.52-
3.32 (m, 1H), 3.05 (quintet, J ) 5.86 Hz, 6.84 Hz, 1H), 2.92-
2.76 (m, 2H), 2.64-2.44 (m, 2H), 1.04 (d, J ) 6.84 Hz, 6H);
EI/MS m/z (r.i.) 391 (M+, 1), 215 (6), 175 (95), 91 (100).
17: 13C NMR δ 157.6, 157.4, 143.9, 142.4, 140.4, 128.2, 128.0,
127.8, 126.8, 126.4, 113.8, 113.7, 55.2, 51.2, 50.6, 49.3, 43.8,
Reaction of the Iminium Ion Intermediate with Ac-
etophenone. Iodine (0.63 g, 2.5 mmol) and N,N-diisopropyl-
N-benzylamine (0.96 g, 5 mmol) were taken in dichloroethane
(40 mL) under N2, and the mixture was refluxed at 95-100
°C for 2 h and brought to 25 °C under N2. TiCl4 (2.2 mL of 1:1
solution of TiCl4-CH2Cl2, 10 mmol) was added at 0 °C followed
by N,N-diisopropyl-N-benzylamine (1.91 g, 10 mmol). The
contents were stirred at 0-25 °C for 1 h. Acetophenone (0.9
mL, 7.5 mmol) was then added at 25 °C and stirred further at
25 °C for 6 h. A saturated NH4Cl solution (20 mL) was added
and stirred for 0.5 h. The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined organic extract was washed with 5 N HCl (2 ×
20 mL) to remove the unreacted amine, followed by water and
brine solution (10 mL), and dried over anhydrous MgSO4. The
solvent was removed, and the residue was chromatographed
on a silica gel column. Unidentified less polar compounds were
1
42.1, 18.9; H NMR δ 7.50-6.78 (m, 13H), 3.83 (s, 3H), 3.79
(s, 3H), 3.63 (s, 2H), 3.54-3.36 (m, 1H), 3.06 (quintet, J ) 5.86
Hz, 6.84 Hz, 1H), 2.94-2.80 (m, 2H), 2.64-2.44 (m, 2H), 1.06
(d, J ) 6.84 Hz, 6H); GCMS, M+ (m/z) 415. 18: 13C NMR δ
152.6, 151.3, 142.3, 139.7, 128.3, 128.1, 127.5, 127.1, 127.0,
126.6, 123.3, 122.6, 119.7, 119.4, 51.0, 50.6, 49.2, 46.4, 41.1,
18.9; 1H NMR δ 7.90-7.24 (m, 13H), 4.26-4.06 (m, 1H), 3.84
(s, 2H), 3.20 (quintet, J ) 5.86 Hz, 6.84 Hz, 1H), 2.86-2.68
(m, 2H), 2.62-2.46 (m, 2H), 1.20 (d, J ) 6.84 Hz, 6H); EI/MS
(16) Michejda, C. J.; Comnick, R. W. J. Org. Chem. 1975, 40, 1046.
5424 J. Org. Chem., Vol. 70, No. 14, 2005
(17) Deno, N. C.; Fruit Jr, R. E. J. Am. Chem. Soc. 1968, 90, 3502.

3,3-Diarylcyclobutanone and 3,3-Diarylcyclobutylamine Derivatives
m/z (r.i.) 353 (M+, 1%), 205 (6%), 174 (100%), 91 (100%). 19:
13C NMR δ 151.4, 148.4, 148.2, 145.0, 142.4, 135.1, 134.8,
129.2, 129.0, 128.3, 128.0, 126.8, 126.4, 125.8, 125.6, 125.3,
on an alumina column. The cyclobutylamine derivative was
isolated by elution with 15% EtOAc-hexane mixture.
21: mp 110-112 °C; 13C NMR δ 148.7, 145.9, 131.8, 131.5,
128.6, 128.5, 128.2, 127.3, 56.2, 43.0, 41.8, 40.5; 1H NMR δ
7.36-7.04 (m, 8H), 3.00-2.84 (m, 2H), 2.74-2.42 (m, 3H), 2.14
(s, 6H); EI/MS m/z (r.i.) 71 (100). 22: mp 82-84 °C; 13C NMR
δ 163.5, 163.3, 158.6, 158.5, 146.4, 143.4, 128.4, 128.2, 127.4,
127.2, 115.3, 115.2, 114.9, 114.8, 56.2, 42.8, 41.8, 40.8; 1H NMR
δ 7.40-6.82 (m, 8H), 3.00-2.82 (m, 2H), 2.74-2.44 (m, 3H),
2.14 (s, 6H); EI/MS m/z (r.i.) 287 (M+, trace), 214 (7), 71 (100).
23: 13C NMR δ 151.0, 148.2, 147.9, 145.0, 135.2, 134.8, 129.1,
128.9, 128.3, 128.2, 126.9, 126.8, 125.9, 125.7, 125.4, 56.6, 43.5,
43.4, 41.9, 40.6, 20.9; 1H NMR δ 7.52-7.04 (m, 9H), 3.10-
2.94 (m, 2H), 2.80-2.50 (m, 3H), 2.20 (s, 6H); EI/MS m/z (r.i.)
265 (M+, 1), 71 (100).
1
51.4, 50.7, 49.3, 44.7, 41.9, 20.9, 18.8; H NMR δ 7.56-7.10
(m, 14H), 3.65 (s, 2H), 3.60-3.40 (m, 1H), 3.18-2.84 (m, 3H),
2.70-2.52 (m, 2H), 2.40 and 2.35 (2 peaks, mixture of two
isomers), 1.08 (d, J ) 6.84 Hz, 6H); EI/MS m/z (r.i.) 369 (M+,
2), 278 (6), 175 (74), 91 (100). 20: mp 132-134 °C; 13C NMR
δ 151.6, 148.3, 148.1, 145.1, 144.8, 142.4, 128.3, 128.1, 127.1,
127.0, 126.8, 126.5, 126.0, 125.8, 125.4, 51.4, 50.9, 50.7, 49.4,
44.9, 44.7, 42.2, 42.0, 19.0; 1H NMR δ 7.60-7.10 (m, 24H), 3.70
(s, 4H), 3.62-3.40 (m, 2H), 3.24-2.88 (m, 6H), 2.76-2.52 (m,
4H), 1.16 (d, J ) 6.84 Hz, 12H). Anal. Calcd for C46H52N2: C,
87.29; H, 8.28; N, 4.43. Found: C, 87.25; H, 8.24; N, 4.48.
Synthesis of N,N-Dimethyl-3,3-diarylcyclobutylamine
Derivatives. The reductive amination of 3,3-diarylcyclo-
butanone derivatives was carried out following a reported
procedure.2 A solution of the 3,3-diaryl cyclobutanone (2.5
mmol) in 5 mL of DMF was added to dimethylammonium
formate [prepared from HCOOH (0.23 g, 5 mmol) and dim-
ethylamine (0.8 g, 17.5 mmol) at -10 °C], and the mixture
was heated under reflux for 5 h. Diethyl ether was added to
the cooled reaction mixture, and the solution was extracted
with 2 M HCl solution. The acidic extracts were made alkaline
using a 50% NaOH solution and extracted with Et2O. The
ether extracts were combined and dried over MgSO4. The
solvent was evaporated, and the residue was chromatographed
Acknowledgment. K.N.J. thanks CSIR (New Delhi)
and P.B. thanks UGC for fellowships. We thank the
DST for support under the FIST program and the UGC
for support under the “University with Potential for
Excellence” program.
Supporting Information Available: 13C NMR spectra of
compounds 4-12 and 14-23. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0504215
J. Org. Chem, Vol. 70, No. 14, 2005 5425