Synthesis of fully-substituted alkenylimidazoles from N-(cyanoalkyl)amides via the In-mediated allylation of nitrile and dehydrative cyclization cascade

Article abstract of DOI:10.1016/j.tetlet.2010.09.016

The reaction of allylindium reagents and N-(cyanoalkyl)amides afforded fully-substituted 4-alkenylimidazoles in moderate yields via the In-mediated Barbier-type allylation of nitrile and the following dehydrative cyclization cascade.

Full text of DOI:10.1016/j.tetlet.2010.09.016

Tetrahedron Letters 51 (2010) 5922–5926
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Tetrahedron Letters
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Synthesis of fully-substituted alkenylimidazoles from N-(cyanoalkyl)amides
via the In-mediated allylation of nitrile and dehydrative cyclization cascade
Yu Mi Kim a, Sangku Lee b, Sung Hwan Kim a, Ko Hoon Kim a, Jae Nyoung Kim a,
⇑
a Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b Natural Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of allylindium reagents and N-(cyanoalkyl)amides afforded fully-substituted 4-alkenylimi-
dazoles in moderate yields via the In-mediated Barbier-type allylation of nitrile and the following dehyd-
rative cyclization cascade.
Received 9 August 2010
Revised 2 September 2010
Accepted 3 September 2010
Available online 15 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkenylimidazoles
Indium
Nitrile
Allylation
Barbier reaction
Imidazole derivatives are important constituents in many bio-
logically active substances and provide a scaffold for designing
drugs, and many functional organic materials.1 Numerous syn-
thetic methodologies of imidazoles are available; however, they
suffer from many drawbacks such as harsh reaction conditions
and multistep synthesis.2,3 Especially the synthesis of imidazoles
having a C-alkenyl moiety required an indirect method; a sequen-
tial regio-controlled halogenation of imidazole, metallation, and
the following introduction of alkenyl moiety.3 The C-alkenylimi-
dazoles can be used for the synthesis of cyclic compounds via the
ring-closing metathesis (RCM) reaction or via the Pd-catalyzed
cyclization.4 Thus, an efficient synthesis of C-alkenylimidazoles in
a direct way is highly required.
Allylindium reagents have been used extensively for the intro-
duction of an allyl group in a Barbier-type manner to various elec-
trophiles.5–7 Although many reactive electrophiles such as
aldehydes and imines have been used in the indium-mediated ally-
lations,5 the reaction of less reactive nitrile has not been reported
much except in the first successful results of Yamamoto and Fujiw-
ara,6 and in our recent papers.7
to form the corresponding imine or enamine intermediates, and the
intermediates can form various cyclic compounds when the mole-
cule has a suitable electrophilic quencher such as an ester7a,d or a
sterically hindered ketone group.7b,c Very recently, we reported an
efficient synthesis of quinazoline derivatives via the In-mediated
Barbier-type allylation and dehydrative cyclization protocol from
N-(ortho-cyanoaryl)amides.7e The results stated that an amide
group could be used as an electrophilic quencher effectively for
the imine intermediate.
Thus we strongly believed that a C-allylimidazole scaffold could
be constructed from N-(cyanoalkyl)amide derivatives 1, as shown
in Scheme 1. The starting materials 1 were prepared by benzoyla-
tion of the corresponding
a
-aminonitriles, which were prepared
from mandelonitrile and amine.8 Some of the
a-aminonitriles were
prepared by addition of KCN to imines, generated in situ from the
corresponding aldehyde and amine in the presence of NaHSO3.9
As shown in Table 1, the reaction of 1a produced an allyl imidaz-
ole 2a and a propenyl derivative 3a in variable yields depending on
the reaction conditions. The highest yield of imidazoles (79%,
2a + 3a) was obtained when the reaction was run with allyl bromide
(3.0 equiv) and indium (1.5 equiv) in refluxing THF for 40 min (entry
2, condition B). In the reaction, 4-allylimidazole 2a was isolated in
62% along with a 1-propenyl derivative 3a in small amounts
(17%).10 The yield and the ratio of 2a/3a seemed to be dependent
on many parameters including solvent, temperature, reaction time,
and the amounts of allylindium reagents (see also Table 2). The reac-
tion in DMF at a higher temperature (entry 4) or the reaction for a
long time (entry 5) reduced the yields of products.
Recently, we reported a series of indium-mediated Barbier-type
allylations of nitrile groups in
c c
-cyanoesters,7a -ketonitriles,7b
d-ketonitriles,7c ortho-cyanobenzoates,7d and N-(ortho-cyanoa-
ryl)amides.7e From the recent studies, we found that the intrinsic
reactivity of a nitrile group toward allylindium reagents is sufficient
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.016

Y. M. Kim et al. / Tetrahedron Letters 51 (2010) 5922–5926
5923
OH
CN
1. R-NH2, EtOH, reflux
2. PhCOCl, pyridine
Ph
N
Ph
N
O
R
R
allyl bromide
In, THF, reflux
Ph
N
N
R
N
Ph
CN
+
Ph
Ph
Ph
1. aq THF, NaHSO 3
R-NH2, KCN, rt
2
1
3
Ph-CHO
2. PhCOCl, pyridine
R = aryl, alkyl
- H2O
O
O
O
R
R
R
N
Ph
N
Ph
N
Ph
NH
NH2
NH2
Ph
Ph
Ph
(I)
(II)
(III)
Scheme 1.
Table 1
Optimization of reaction conditions
Cl
Cl
Cl
Ph
N
Ph
O
Conditions
N
N
+
N
N
Ph
CN
Ph
Ph
Ph
1a
Conditionsa
3a
2a
Entry
Yield (2a:3a)b
1
2
Allyl bromide (2.0 equiv), In (1.0 equiv), THF, reflux, 60 min (condition A)
Allyl bromide (3.0 equiv), In (1.5 equiv), THF, reflux, 40 min (condition B)
Allyl bromide (4.0 equiv), In (2.0 equiv), THF, reflux, 60 min (condition C)
Allyl bromide (4.0 equiv), In (2.0 equiv), 120–130 °C, 60 min
51:25
62:17
59:5
42:4
35:14
3
4c
5
Allyl bromide (3.0 equiv), In (1.5 equiv), THF, reflux, 300 min
a
b
c
Reactions were carried out under N2 atmosphere for the given time.
Isolated yield.
The reaction in DMF at 60–70 °C showed sluggish reactivity.
Cl
Cl
7
Cl
Ph
Ph
N 3
Ph
3
N
1
N
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
3
N
N
8
1
N
1
+
2f
+
Cs2CO3 (2.0 equiv)
toluene, reflux, 3 h
5
Me
4 (46%)
1H-naphtho[1,2-d]imidazole
5 (9%)
imidazo[1,5-f ]phenanthridine
6 (5%)
3,8-dihydroindeno[1,2-d]imidazole
same conditions
3f
4 (10%) + 5 (45%) + 6 (25%)
Scheme 2.
The reaction mechanism could be suggested as an indium-med-
tion of (I) to the enamine intermediates (II) and (III) prior to the
iated Barbier-type allylation of nitrile to form imine or enamine
intermediates (I)–(III) and the following dehydrative cyclization,
as shown in Scheme 1. Attempted isomerization of 2a into 3a failed
under basic (DBU, CH3CN, reflux)7e and acidic conditions (p-TsOH,
toluene, reflux). In addition, exposure of 2a under the influence of
allylindium reagents (allyl bromide, In, THF, reflux) did not pro-
duce 3a at all. The results stated that the isomerization of allyl to
1-propenyl group might occur prior to the formation of the imidaz-
ole ring. Thus we proposed the mechanism involving an isomeriza-
dehydrative cyclization step, tentatively.
Encouraged by the results we prepared various N-benzoyl
a-
aminonitriles 1b–f,8,9 and examined the reactions with allylindium
(or methallylindium) reagents, and the results are summarized in
Table 2. The reactions of 1b–f (entries 2–6) and allylindium re-
agents showed similar results to that of 1a. The reactions under
condition B showed higher combined yields (2 + 3) than under
the other conditions in most entries. Starting materials remained
in some entries under condition A (entries 2 and 4). Methallyl bro-

5924
Y. M. Kim et al. / Tetrahedron Letters 51 (2010) 5922–5926
Table 2
Synthesis of alkenylimidazole derivatives
Entry
Substrate (%)a
Products (2 + 3)
Conditions: yield (%)
A: 2a (51), 3a (25)
B: 2a (62), 3a (17)
C: 2a (59), 3a (5)
Cl
Cl
Cl
O
Ph
N
Ph
N
N
Ph
N
N
1
Ph
CN
Ph
Ph
1a (88)
2a
3a
O
Ph
Ph
A: 2b (35), 3b (25), 1b (15)
B: 2b (40), 3b (23)
C: 2b (39), 3b (8)
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
Ph
N
N
2
3
CN
1b (87)
2b
3b
Me
B: 2c (30), 3c (25)
C: 2c (21), 3c (13)
Me
Me
O
Ph
N
Ph
N
N
Ph
N
N
Ph
CN
Ph
Ph
1c (85)
2c
3c
O
Ph
N
Ph
A: 2d (37), 3d (26), 1d (20)
B: 2d (36), 3d (30)
C: 2d (37), 3d (13)
Ph
N
Ph
N
Ph
N
Ph
N
4
5
Ph
Ph
Ph
CN
1d (89)
2d
3d
O
Ph
N
Ph
N
N
Ph
N
N
B: 2e (40), 3e (21)
Ph
CN
Ph
Ph
1e (51)
2e
Cl
3e
Cl
Cl
O
Ph
N
Ph
N
N
Ph
CN
N
N
6
B: 2f (41), 3f (27)
Br
1f (78)
Br
Br
2f
3f
Cl
Cl
B: 2g (50), 3g (À)
C: 2g (54), 3g (À)
Ph
N
Ph
N
N
N
7b
1a
Ph
Ph
2g
3g
a
Starting materials were prepared as reported,8,9 and the yield refer to benzoylation of the corresponding
Methallyl bromide was used.
a-aminonitriles.
b
mide could be used in the same manner to form 2-isobutenylimi-
dazole 2g; however, the corresponding 1-isobutenyl derivative 3g
was not formed (entry 7), but the reason is not clear at this stage.
In order to show the synthetic applicability of the synthesized
C-alkenylimidazoles we carried out the Pd-catalyzed cyclizations
of compounds 2f and 3f, as shown in Scheme 2. The Pd-catalyzed
cyclization of 2f produced three compounds 4–6.10,11 The forma-
tion of 1H-naphtho[1,2-d]imidazole 4 (46%) could be explained
via the sequential 6-exo-trig carbopalladation of the arylpalladium
intermediate (IV), b-H elimination to form (V), and double bond
isomerization,12,13 as shown in Scheme 3. Imidazo[1,5-f]phenan-
thridine derivative 5 (9%) must be formed via the aryl–aryl
coupling of (IV) to form (VII) and isomerization of allyl to 1-prope-
nyl group.12 A trace amount of indeno[1,2-d]imidazole derivative 6
(5%) was also formed most likely via the initial isomerization of al-
lyl to 1-propenyl and the following 5-exo-trig cyclization of (VI).
It is interesting to note that the same compounds 4–6 were
formed in the reaction of 1-propenyl derivative 3f, albeit in a dif-
ferent products’ ratio. The plausible mechanism for the formation
of 4–6 from 3f is also summarized in Scheme 3. The compound 5
was formed as a major product (45%) via an aryl–aryl coupling of
(VI), and 6 was formed (25%) via the 5-exo-trig carbopalladation
of (VI). The formation of 4 (10%) could be the result of 6-endo-trig
cyclization of (VI) or 6-exo-trig cyclization of (IV). All of the above
double bond isomerization processes might be catalyzed by HPdBr
formed in the reaction progress. Such an isomerization catalyzed
by hydrido palladium bromide (HPdBr) species has been known
in many examples.12

Y. M. Kim et al. / Tetrahedron Letters 51 (2010) 5922–5926
5925
3f
2f
Pd0
Pd0
Cl
Cl
Cl
Ph
Ph
N
Ph
N
N
N
6-exo
5-exo
N
N
4
6
46% from 2f
10% from 3f
5% from 2f
25% from 3f
Pd
Br
(VI)
Pd
Br
(IV)
(V)
aryl-aryl
aryl-aryl
Cl
Ph
N
N
5
9% from 2f
45% from 3f
(VII)
Scheme 3.
28, 17–28; (d) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149–11176; (e) Pae,
A. N.; Cho, Y. S. Curr. Org. Chem. 2002, 6, 715–737; (f) Nair, V.; Ros, S.; Jayan, C.
N.; Pillai, B. S. Tetrahedron 2004, 60, 1959–1982; (g) Podlech, J.; Maier, T. C.
Synthesis 2003, 633–655.
In summary, a facile synthesis of fully-substituted C-alkenylim-
idazoles has been disclosed starting from N-(cyanoalkyl)amides in
moderate yields via the In-mediated Barbier-type allylation of
nitrile and the following dehydrative cyclization cascade.
6. (a) Fujiwara, N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 4729–4732; (b)
Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4095–4101.
7. For the In-mediated Barbier-type allylation of nitrile-containing substrates,
see: (a) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50,
1696–1698; (b) Kim, S. H.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett.
2009, 50, 5744–5747; (c) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron
Lett. 2009, 50, 6476–6479; (d) Kim, S. H.; Kim, S. H.; Kim, K. H.; Kim, J. N.
Tetrahedron Lett. 2010, 51, 860–862; (e) Kim, S. H.; Kim, S. H.; Kim, T. H.; Kim, J.
N. Tetrahedron Lett. 2010, 51, 2774–2777; (f) Kim, S. H.; Lee, H. S.; Kim, K. H.;
Kim, S. H.; Kim, J. N. Tetrahedron 2010, 66, 7065–7076.
Acknowledgments
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2010-0015675). Spectroscopic data were obtained from the Korea
Basic Science Institute, Gwangju branch.
8. For the synthesis of
a-amino nitriles from mandelonitrile derivatives, see: (a)
McEwen, W. E.; Grossi, A. V.; MacDonald, R. J.; Stamegna, A. P. J. Org. Chem.
1980, 45, 1301–1308; (b) Langridge, D. C.; Hixson, S. S.; McEwen, W. E. J. Org.
Chem. 1985, 50, 5503–5507; (c) Cooney, J. V.; McEwen, W. E. J. Org. Chem. 1981,
46, 2570–2573.
References and notes
9. For the synthesis of
a-amino nitriles from aldimines (the Strecker reaction),
1. For the synthesis of imidazoles and their biological activities, see: (a)
Grimmett, M. R. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic: New York, 1980; Vol. 27, p 241; (b) Grimmett,
M. R.. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J., Eds.;
Academic: New York, 1970; Vol. 12, p 103; (c) Weinreb, S. M. Nat. Prod. Rep.
2007, 24, 931–948; (d) Du, H.; He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965–
992; (e) Gosselin, F.; Lau, S.; Nadeau, C.; Trinh, T.; O’Shea, P. D.; Davies, I. W. J.
Org. Chem. 2009, 74, 7790–7797; (f) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.;
Lovely, C. J. Org. Lett. 2008, 10, 5055–5058; (g) Shilcrat, S. C.; Mokhallalati, M.
K.; Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449–8454; (h)
Aberle, N.; Catimel, J.; Nice, E. C.; Watson, K. G. Bioorg. Med. Chem. Lett. 2007, 17,
3741–3744.
2. For the leading references on the synthesis of imidazole derivatives, see: (a)
Kanazawa, C.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2006, 128, 10662–
10663; (b) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977,
42, 1153–1159; (c) Kison, C.; Opatz, T. Chem. Eur. J. 2009, 15, 843–845; (d)
Zhong, Y.-L.; Lee, J.; Reamer, R. A.; Askin, D. Org. Lett. 2004, 6, 929–931; (e)
Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer, R. D.
Org. Lett. 2004, 6, 843–846; (f) Zaman, S.; Mitsuru, K.; Abell, A. D. Org. Lett.
2005, 7, 609–611; (g) Gwiazda, M.; Reissig, H.-U. Synthesis 2008, 990–994; (h)
Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216–2220.
3. For the synthesis of alkenylimidazoles, see: (a) Yang, X.; Knochel, P. Chem.
Commun. 2006, 2170–2172; (b) Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron
Lett. 1999, 40, 7449–7453; (c) Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.;
Rottlander, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618–4634; (d) Chittiboyina,
A. G.; Reddy, C. R.; Watkins, E. B.; Avery, M. A. Tetrahedron Lett. 2004, 45, 1869–
1872; (e) Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345–346; (f) Turner,
R. M.; Ley, S. V.; Lindell, S. D. Synlett 1993, 748–750.
see: (a) Leblanc, J.-P.; Gibson, H. W. J. Org. Chem. 1994, 59, 1072–1077; (b)
Spaltenstein, A.; Holler, T. P.; Hopkins, P. B. J. Org. Chem. 1987, 52, 2977–2979;
(c) Naim, S. S.; Sharma, S. Synthesis 1992, 664–666; (d) Wiles, C.; Watts, P. Eur. J.
Org. Chem. 2008, 5597–5613; (e) Niknam, K.; Saberi, D.; Sefat, M. N. Tetrahedron
Lett. 2010, 51, 2959–2962; (f) Groger, H. Chem. Rev. 2003, 103, 2795–2827 and
further references cited therein; (g) Li, Z.; Ma, Y.; Xu, J.; Shi, J.; Cai, H.
Tetrahedron Lett. 2010, 51, 3922–3926.
10. Typical procedure for the synthesis of 2a and 3a: A stirred mixture of 1a (173 mg,
0.5 mmol), allyl bromide (182 mg, 1.5 mmol), and indium (86 mg, 0.75 mmol)
in THF (1.0 mL) was heated to reflux for 40 min. After the usual aqueous
workup and column chromatographic purification process (hexanes/CH2Cl2/
EtOAc, 10:1:1), we obtained compound 2a (115 mg, 62%) and 3a (32 mg, 17%)
as a white solid. Other compounds were synthesized similarly, and the selected
spectroscopic data of 2a, 3a, 2d, 3d, 2f, 3f, and 2g are as follows.
Compound 2a: 62%; white solid, mp 168–170 °C; IR (KBr) 1600, 1493, 1466,
1443 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.43 (dt, J = 6.3 and 1.5 Hz, 2H), 5.05–
;
5.17 (m, 2H), 6.07–6.20 (m, 1H), 6.90–6.95 (m, 2H), 7.03–7.09 (m, 2H), 7.18–
7.29 (m, 8H), 7.30–7.35 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 32.15, 115.44,
127.54, 128.10, 128.13, 128.20, 128.93, 129.29, 129.33, 129.68, 130.23, 130.34,
130.67, 133.80, 135.87, 136.92, 138.06, 146.41; ESIMS m/z 371 (M++H), 373
(M++H+2). Anal. Calcd for C24H19ClN2: C, 77.72; H, 5.16; N, 7.55. Found: C,
77.96; H, 5.25; N, 7.39.
Compound 3a: 17%; white solid, mp 149–151 °C; IR (KBr) 1593, 1493,
1445 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.86 (dd, J = 6.6 and 1.5 Hz, 3H),
;
6.33 (dd, J = 15.6 and 1.5 Hz, 1H), 6.61–6.72 (m, 1H), 6.90–6.96 (m, 2H), 7.07–
7.10 (m, 2H), 7.20–7.30 (m, 8H), 7.35–7.38 (m, 2H); 13C NMR (CDCl3, 75 MHz) d
18.42, 121.46, 126.10, 127.68, 128.18, 128.25, 128.43, 129.07, 129.36 (2C),
129.44, 130.30, 130.55, 133.93, 135.68, 137.62, 147.17 (one carbon is
overlapped); ESIMS 371 (M++H), 373 (M++H+2). Anal. Calcd for C24H19ClN2:
C, 77.72; H, 5.16; N, 7.55. Found: C, 77.85; H, 5.32; N, 7.51.
4. For the RCM and Pd-catalyzed reactions of alkenylimidazoles, see: (a) Gracias,
V.; Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005, 7, 3183–3186; (b) Chen, Y.;
Rasika, H. V.; Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379–1382; (c) Lovely, C. J.;
Chen, Y.; Ekanayake, E. V. Heterocycles 2007, 74, 873–894; (d) Beebe, X.;
Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 3225–3228.
5. For the general review on indium-mediated reactions, see: (a) Auge, J.; Lubin-
Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (b) Kargbo, R. B.; Cook, G. R.
Curr. Org. Chem. 2007, 11, 1287–1309; (c) Lee, P. H. Bull. Korean Chem. Soc. 2007,
Compound 2d: 36%; pale yellow oil; IR (film) 1670, 1496, 1452, 1400 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 3.36 (dt, J = 6.3 and 1.5 Hz, 2H), 4.95–5.11 (m, 2H),
5.13 (s, 2H), 6.00–6.13 (m, 1H), 6.72–6.75 (m, 2H), 7.11–7.24 (m, 5H), 7.26–
7.40 (m, 6H), 7.54–7.60 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 32.02, 48.36,
115.06, 125.88, 127.17, 127.97, 128.30, 128.37, 128.44, 128.58, 128.90, 130.18,

5926
Y. M. Kim et al. / Tetrahedron Letters 51 (2010) 5922–5926
1276 cmÀ1
130.31, 130.40, 130.93, 137.06, 137.63, 137.67, 147.74; ESIMS m/z 351 (M++H).
;
1H NMR (CDCl3, 300 MHz) d 2.79 (s, 3H), 7.22–7.35 (m, 5H), 7.36–
Anal. Calcd for C25H22N2: C, 85.68; H, 6.33; N, 7.99. Found: C, 85.56; H, 6.57; N,
7.72.
7.57 (m, 7H), 7.82 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
20.30, 120.09, 120.36, 122.12, 124.20, 125.40, 125.69, 128.27, 129.04, 129.30,
129.36, 130.13, 130.33 (2C), 130.38, 130.87, 135.58, 137.40, 140.13, 151.31;
ESIMS m/z 369 (M++H), 371 (M++H+2). Anal. Calcd for C24H17ClN2: C, 78.15; H,
4.65; N, 7.59. Found: C, 78.41; H, 4.77; N, 7.48.
Compound 3d: 30%; pale yellow oil; IR (film) 1603, 1496, 1488, 1451 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 1.81 (dd, J = 6.6 and 1.5 Hz, 3H), 5.11 (s, 2H), 6.23 (dd,
J = 15.6 and 1.5 Hz, 1H), 6.52–6.64 (m, 1H), 6.71–6.75 (m, 2H), 7.12–7.17 (m,
4H), 7.19–7.25 (m, 2H), 7.30–7.42 (m, 5H), 7.53–7.62 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 18.33, 48.32, 121.73, 124.98, 126.00, 127.27, 128.10, 128.46, 128.48
(2C), 128.83, 129.07, 129.96, 130.17, 130.57, 130.97, 137.44, 137.51, 148.61;
ESIMS m/z 351 (M++H). Anal. Calcd for C25H22N2: C, 85.68; H, 6.33; N, 7.99.
Found: C, 85.86; H, 6.16; N, 7.87.
Compound 5: 9%; pale yellow solid, mp 208–210 °C; IR (KBr) 1541, 1458,
1274 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.03 (dd, J = 6.6 and 1.5 Hz, 3H), 6.73–
;
6.84 (m, 1H), 7.00 (dd, J = 15.6 and 1.5 Hz, 1H), 7.07 (dd, J = 9.0 and 2.4 Hz, 1H),
7.30 (d, J = 9.0 Hz, 1H), 7.42–7.65 (m, 7H), 8.12–8.15 (m, 1H), 8.17 (d, J = 2.4 Hz,
1H), 8.23 (dd, J = 8.1 and 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 18.82, 119.89,
122.76, 122.84, 122.95, 123.79, 124.11, 125.36, 125.59, 126.58, 126.69, 127.59,
129.07, 129.25, 129.36, 129.55, 129.70, 130.75, 130.90, 133.32, 134.39, 143.24;
ESIMS m/z 369 (M++H), 371 (M++H+2). Anal. Calcd for C24H17ClN2: C, 78.15; H,
4.65; N, 7.59. Found: C, 78.21; H, 4.90; N, 7.38.
Compound 2f: 41%; white solid, mp 121–122 °C; IR (KBr) 1605, 1494,
1467 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.22–3.40 (m, 2H), 4.95–5.08 (m,
;
2H), 5.95–6.08 (m, 1H), 6.96–7.00 (m, 2H), 7.14–7.27 (m, 8H), 7.36–7.40 (m,
2H), 7.53–7.56 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 32.41, 115.57, 126.57,
127.03, 128.15, 128.28, 128.75, 129.04, 129.12, 129.82, 130.20, 130.35, 131.30,
132.64, 133.72, 133.86, 135.74, 135.99, 138.61, 146.43; ESIMS m/z 449 (M++H),
451 (M++H+2), 453 (M++H+4). Anal. Calcd for C24H18BrClN2: C, 64.09; H, 4.03;
N, 6.23. Found: C, 64.24; H, 4.11; N, 6.17.
Compound 6: 5%; pale yellow solid, mp 198–199 °C; IR (KBr) 1541, 1508, 1398,
1274 cmÀ1 1H NMR (CDCl3, 300 MHz)
; d 2.58 (d, J = 7.2 Hz, 3H), 6.68 (q,
J = 7.2 Hz, 1H), 6.78–6.81 (m, 1H), 7.05–7.15 (m, 2H), 7.24–7.36 (m, 5H), 7.41–
7.48 (m, 4H), 7.59–7.61 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 16.05, 116.30,
120.46, 124.85, 126.79, 128.02, 128.35, 128.47, 128.71, 129.10, 129.21, 129.90,
130.31, 134.51, 136.25, 138.99, 140.31, 145.77, 150.52 (one carbon is
overlapped); ESIMS m/z 369 (M++H), 371 (M++H+2). Anal. Calcd for
Compound 3f: 27%; white solid, mp 79–80 °C; IR (KBr) 1597, 1493, 1446 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 1.82 (dd, J = 6.6 and 1.5 Hz, 3H), 6.06 (dd, J = 15.6
and 1.5 Hz, 1H), 6.48–6.60 (m, 1H), 6.94–6.99 (m, 2H), 7.14–7.32 (m, 8H), 7.35–
7.43 (m, 2H), 7.55–7.59 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 18.41, 121.44,
125.91, 126.46, 127.15, 128.19, 128.46, 128.85, 129.02, 129.13, 129.26, 130.13,
130.40, 131.05, 132.80, 133.71, 133.90, 135.51, 138.15, 147.06; ESIMS m/z 449
(M++H), 451 (M++H+2), 453 (M++H+4). Anal. Calcd for C24H18BrClN2: C, 64.09;
H, 4.03; N, 6.23. Found: C, 64.37; H, 4.14; N, 6.07.
C
24H17ClN2: C, 78.15; H, 4.65; N, 7.59. Found: C, 78.36; H, 4.89; N, 7.52.
11. For the synthesis and biological activities of similar compounds, see: (a) Toja,
E.; Di Francesco, G.; Barone, D.; Baldoli, E.; Corsico, N.; Tarzia, G. Eur. J. Med.
Chem. 1987, 22, 221–228; (b) Michael, F. U.S. 4548943, 1985; Chem. Abstr.
1986, 104, 75034
Compound 2g: 50%; white solid, mp 162–163 °C; IR (KBr) 1600, 1493,
12. For the examples on double bond isomerization during the Pd-catalyzed
cyclizations caused by HPdX species, see: (a) Huang, Q.; Larock, R. C. J. Org.
Chem. 2003, 68, 7342–7349; (b) Larock, R. C.; Takagi, K.; Burkhart, J. P.;
Hershberger, S. S. Tetrahedron 1986, 42, 3759–3762; (c) Yip, K.-T.; Zhu, N.-Y.;
Yang, D. Org. Lett. 2009, 11, 1911–1914; (d) Nasveschuk, C. G.; Frein, J. D.; Jui, N.
T.; Rovis, T. Org. Lett. 2007, 9, 5099–5102; (e) Soderberg, B. C. G.; Hubbard, J.
W.; Rector, S. R.; O’Neil, S. N. Tetrahedron 2005, 61, 3637–3649; (f) Soderberg,
B. C. G.; Rector, S. R.; O’Neil, S. N. Tetrahedron Lett. 1999, 40, 3657–3660; (g) Shi,
L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48,
3894–3900.
13. Trials for the separation of the exo-methylene intermediate (V) in the reaction
mixture failed. In order to reduce the HPdBr-catalyzed isomerization process,12
we carried out the reaction of 2f in the presence of an organic base (Et3N,
toluene, reflux, 24 h). However, we failed again to obtain (V) in an appreciable
amount. The reaction was somewhat slow, and compounds 4 (25%), 5 (6%), and
6 (24%) were isolated.
1443 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.81 (s, 3H), 3.35 (s, 2H), 4.75 (s,
;
1H), 4.84 (s, 1H), 6.92–6.96 (m, 2H), 7.05–7.08 (m, 2H), 7.19–7.25 (m, 8H),
7.32–7.36 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 22.87, 35.80, 111.42, 127.50,
128.06, 128.10, 128.14, 128.94, 129.28, 129.36, 129.81, 130.13, 130.39, 131.27,
133.77, 135.96, 137.83, 144.59, 146.30; ESIMS m/z 385 (M++H), 387 (M++H+2).
Anal. Calcd for C25H21ClN2: C, 78.01; H, 5.50; N, 7.28. Found: C, 78.33; H, 5.71;
N, 7.23.
Typical procedure for the Pd-catalyzed reaction of 2f: A stirred mixture of 2f
(180 mg, 0.4 mmol), Pd(OAc)2 (9 mg, 10 mol %), PPh3 (21 mg, 20 mol %), Cs2CO3
(260 mg, 0.8 mmol) in toluene (1.5 mL) was heated to reflux for 3 h. After the
usual aqueous workup and column chromatographic purification process
(hexanes/CH2Cl2/EtOAc, 20:2:1), we obtained compound 4 (68 mg, 46%), 5
(13 mg, 9%), and 6 (7 mg, 5%) as pale yellow solids. The reaction of 3f was
carried out similarly, and the spectroscopic data of 4–6 are as follows.
Compound 4: 46%; pale yellow solid, mp 197–198 °C; IR (KBr) 1541, 1508,