The Journal of Organic Chemistry
ARTICLE
(75 MHz, acetone-d6) δ 145.0, 137.6, 136.4, 129.9, 128.2, 127.1 (2), 124.2,
122.3, 121.2, 76.2, 66.6, 36.4, 31.3, 31.1, 29.1, 18.1, ꢀ1.4; LRMS (ESIþ)
m/z (relative intensity) 412.1 (M þ Hþ 100%); HRMS (ESI) m/z calcd for
[C22H30N3OSSi]þ, 412.1879; found, 412.1879.
(t, J = 8.16 Hz, 2H), ꢀ0.027 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
143.0, 142.9, 126.4, 123.0, 121.9, 118.0, 74.9, 66.2, 35.4, 30.3, 29.6, 28.0,
17.6, 17.1, ꢀ1.50; LRMS (ESIþ) m/z (relative intensity) 350.2
(M þ Hþ, 100%).
4,5-Dibromo-N-((6-(2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-imidazol-5-yl)cyclohex-3-enyl)methyl)-1H-pyrrole-2-carboxa-
mide (52d). Following General Procedure 6, nitrile 50d (65.0 mg,
0.186 mmol) was converted into 65.0 mg (100%) of the corresponding
N-SEM amine, which was obtained as a clear and colorless oil. The product
was used in the acylation reaction without further purification.
4,5-Dibromo-N-((6-(2-(phenylthio)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-imidazol-5-yl)cyclohex-3-enyl)methyl)-
1H-pyrrole-2-carboxamide (52c). Following General Procedure 6,
N-SEM nitrile 50c (1.55 g, 3.78 mmol) was converted to 1.48 g (94% yield)
of crude N-SEM amine 51c, which was obtained as a clear and colorless oil:
IR (thin film) 3376, 3295 cmꢀ1; 1H NMR(300 MHz, CDCl3) δ7.22ꢀ7.20
(m, 2H), 7.13ꢀ7.09 (m, 3H), 6.97 (s, 1H), 5.69 (brs, 2H), 5.27 (s, 2H),
3.29 (t, J = 8.2 Hz, 2H), 2.81ꢀ2.73 (m, 1H), 2.62 (dd, J = 12.9, 3.8 Hz, 1H),
2.49 (dd, J = 12.9, 6.4 Hz, 1H), 2.42ꢀ2.33 (m, 1H), 2.39ꢀ2.27 (m, 1H),
2.16ꢀ2.09 (m, 1H), 2.02ꢀ1.89 (m, 2H), 1.32 (brs, 2H), 0.75 (t, J = 8.2 Hz,
2H), ꢀ0.11 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 147.4, 136.6, 135.3,
129.1, 127.4, 126.4, 126.1, 125.9, 118.5, 75.4, 66.1, 45.4, 40.8, 36.2, 31.3, 28.4,
17.6, ꢀ1.6; LRMS (ESIþ) m/z (relative intensity) 416.2 (M þ Hþ 100).
Following General Procedure 7, N-SEM amine 51c (1.00 g, 2.41
mmol) from above was converted into 1.37 g (85%) of amide 52c, which
was obtained as a white solid following purification of the crude material
by silica gel column chromatography using 30 ꢀ 50% EtOAc in hexanes
as the eluent: mp 175ꢀ176 °C; IR (thin film) 3295, 3113, 2951,
Following General Procedure 7, the crude amine from above
(56.0 mg, 0.186 mmol) was converted into 70.0 mg (63%) of amide
52d, which was obtained as a tacky solid following purification of the
crude substance by silica gel column chromatography using 50% Et2O in
hexanes as the eluent: IR (thin film) 3304, 3113, 1634 cmꢀ1; 1H NMR
(300 MHz, CDCl3) δ 11.8 (s, 1H), 7.90 (brs, 1H), 6.82 (s, 1H), 6.73 (s,
1H), 5.68 (brs, 2H), 5.18 (s, 2H), 3.79ꢀ3.67 (m, 1H), 3.50 (t, J = 8.10
Hz, 2H), 3.08ꢀ2.96 (m, 1H), 2.82ꢀ2.68 (m, 1H), 2.58 (brs, 3H),
2.35ꢀ2.25 (m, 2H), 2.21ꢀ2.01 (m, 3H), 1.95ꢀ1.80 (m, 1H), 0.90 (t, J =
8.07 Hz, 2H), ꢀ0.02 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 159.6,
145.8, 143.0, 127.7, 126.7, 126.0, 117.1, 112.1, 105.0, 99.2, 74.9, 66.4,
42.1, 41.0, 37.1, 31.4, 30.7, 17.6, 16.6, ꢀ1.45; LRMS (ESIþ) m/z
(relative intensity) 603.1 (M þ Hþ, 100%).
1
1634 cmꢀ1; H NMR (300 MHz, CDCl3) δ 11.7 (s, 1H), 7.77 (dd,
J = 7.9, 4.2 Hz, 1H), 7.33ꢀ7.25 (m, 4H), 7.21ꢀ7.15 (m, 1H), 7.03 (s,
1H), 6.56 (d, J = 2.7 Hz, 1H), 5.75 (brs, 2H), 5.34 (s, 2H), 3.84ꢀ3.75
(m, 1H), 3.44 (t, J = 8.2 Hz, 2H), 3.03 (td, J = 14.7, 4.1 Hz, 1H),
2.89ꢀ2.80 (m, 1H), 2.50ꢀ2.24 (m, 2H), 2.23ꢀ2.08 (m, 2H),
2.03ꢀ1.96 (m, 1H), 0.88 (t, J = 8.2 Hz, 2H), 0.00 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 159.6, 146.7, 138.5, 133.8, 129.3, 129.2, 127.4,
127.3, 126.7, 125.8, 118.0, 112.4, 104.9, 99.3, 75.5, 66.4, 42.1, 40.8, 37.0,
31.3, 30.6, 17.7, ꢀ1.5; LRMS (ESIþ) m/z (relative intensity) 665.0611
(M þ Hþ 100).
4,5-Dibromo-N-((6-(2-(methylthio)-1H-imidazol-5-yl)-
cyclohex-3-enyl)methyl)-1H-pyrrole-2-carboxamide (32).
Following General Procedure 8, N-SEM imidazole 52d (60.0 mg,
0.099 mmol) was converted into 29.0 mg (61%) of N-H imidazole 32,
which was obtained as a clear and colorless film following purifica-
tion of the crude residue by silica gel column chromatography using
30 ꢀ 50% EtOAc in hexanes as the eluent: IR (thin film) 3114,
1
1626 cmꢀ1; H NMR (300 MHz, MeOD) δ 7.32 (s, 1H), 6.73 (s,
1H), 5.74 (brs, 2H), 3.36ꢀ3.31 (m, 1H), 3.10 (dd, J = 13.8, 6.3 Hz, 1H),
2.92ꢀ2.84 (m, 1H), 2.67 (s, 3H), 2.42ꢀ2.18 (m, 4H), 1.98ꢀ1.89 (m,
1H); 13C NMR (75 MHz, MeOD) δ 161.5, 143.8, 139.8, 128.5, 126.9,
125.9, 118.4, 114.2, 106.2, 100.0, 44.1, 38.5, 35.8, 31.9, 30.0, 16.3; LRMS
(ESIþ) m/z (relative intensity) 473.0 (M þ Hþ, 100%); HRMS (ESI)
m/z calcd for [C16H19Br2N4OS]þ, 472.9635; found, 472.9646.
Pummerer Reaction-Derived Pentacycles 57a and 57b. In
a 25 mL round-bottom flask, (i-Pr)2NEt (0.0400 mL, 0.228 mmol) was
added dropwise to a solution of 29 (0.0598 g, 0.114 mmol) in 1.5%
CH3OH/CH2Cl2 (10 mL) at 25 °C. Stang’s reagent (PhI(CN)OTf,
0.0220 g 0.0570 mmol) was added to the reaction solution. Additional
portions of PhI(CN)OTf (total of 4.00 equiv) and (i-Pr)2NEt (4.00
equiv) were added over 6 h, at which time the starting material was
determined by TLC to be completely consumed. At that time, the
reaction solution was partitioned between CH2Cl2 and water and the
aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL). The organic
layers were combined, dried over Na2SO4, and concentrated under
reduced pressure to give a colorless oil. The colorless oil was purified by
SiO2 flash column chromatography (CH2Cl2 then 10ꢀ30% Et2O/
CH2Cl2 as eluent) to give 57a (0.012 g, 20%) and 57b (0.0060 g,
10%) as colorless oils.
4,5-Dibromo-N-((6-(2-(phenylthio)-1H-imidazol-5-yl)-
cyclohex-3-enyl)methyl)-1H-pyrrole-2-carboxamide (31).
Following general procedure 8, N-SEM imidazole 52c (1.36 g, 2.04
mmol) was converted into 740 mg (68%) of NꢀH imidazole 31, which
was obtained as a white solid following purification of the crude
material by silica gel column chromatography using 30ꢀ50% EtOAc
in hexanes as the eluent. Spectroscopic data for this product matched
those reported for compound 31 that was prepared from 53.
6-(2-(Methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-
1H-imidazol-5-yl)cyclohex-3-enecarboxamide (49d). Following
General Procedure 4, R,β-unsaturated amide 48 (501 mg, 1.65 mmol)
was converted into 230 mg (38%) of DielsꢀAlder adduct 49d, which was
obtained as a brown solid following purification of the crude material by silica
gel column chromatography using 30ꢀ50% EtOAc in hexanes as the eluent:
1
mp 61ꢀ62 °C; IR (thin film) 3337, 3190, 2925, 1668 cmꢀ1; H NMR
(300 MHz, CDCl3) δ 6.82 (s, 1H), 6.02 (brs, 1H), 5.69 (s, 2H), 5.65 (brs,
1H), 5.21 (d, J = 10.7 Hz, 1H), 5.15 (d, J = 10.7 Hz, 1H), 3.45 (t, J = 8.0 Hz,
2H), 2.95ꢀ2.87 (m, 1H), 2.86ꢀ2.78 (m, 1H), 2.50ꢀ2.38 (m, 5H), 2.20
(m, 2H), 0.86(t, J= 8.1 Hz, 2H), 0.05 (s, 9H); 13CNMR(75MHz, CDCl3)
δ 177.9, 144.6, 142.1, 125.8, 125.1, 118.2, 74.9, 66.1, 45.4, 36.7, 31.9, 28.5,
17.6, 17.5, ꢀ1.52; LRMS (ESIþ) m/z (relative intensity) 368.1 (M þ Hþ,
100%); HRMS (ESI) m/z calcd for [C17H30N3O2SSi]þ, 368.1823; found,
368.1828.
57a: IR (thin film) 3201, 1654 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
7.53ꢀ7.41 (m, 5H), 6.99 (s, 1H), 5.68 (s, 1H), 5.54 (s, 1H), 3.98 (dd, J =
12.0, 9.5 Hz, 1H), 3.59 (dd, J = 12.1, 4.4 Hz, 1H), 3.04 (m, 1H), 2.56 (q,
J = 8.4 Hz, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 1.59ꢀ1.50
(m, 2H), 1.35 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.5,
135.2, 130.8, 130.5, 127.3, 126.3, 115.3., 104.1, 103.0, 96.0, 70.4, 55.5,
51.2, 39.2, 33.8, 29.7, 26.3; LRMS (ESI) m/z (relative intensity) 521.0
(100%, M þ Hþ); HRMS (ESI) m/z calcd for [C20H19Br2N4OS]þ,
520.9646; found, 520. 9662.
6-(2-(Methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
imidazol-5-yl)cyclohex-3-enecarbonitrile (50d). Following
General Procedure 5, amide 49d (230 mg, 0.626 mmol) was converted
into 164 mg (75%) of nitrile 50d, which was obtained as a clear and
colorless oil following purification of the crude material by silica gel
column chromatography using 20% EtOAc in hexanes as the eluent: IR
1
(thin film) 2240 cmꢀ1; H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H),
57b: IR (thin film) 3568, 1654 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ
7.51ꢀ7.40 (m, 5H), 6.98 (s, 1H), 5.70 (s, 1H), 5.46 (s, 1H), 4.26 (dd,
J = 11.9, 9.2 Hz, 1H), 3.32 (dd, J = 11.8, 6.9 Hz, 1H), 2.96 (m, 1H), 2.79
5.80ꢀ5.77 (m, 1H), 5.64ꢀ5.60 (m, 1H), 5.30ꢀ5.15 (m, 2H), 3.49 (t, J =
8.16 Hz, 2H), 3.17ꢀ3.05 (m, 2H), 2.54 (s, 3H), 2.50ꢀ2.32 (m, 4H), 0.90
5057
dx.doi.org/10.1021/jo200740b |J. Org. Chem. 2011, 76, 5042–5060