A Hofmann Rearrangement-Ring Expansion Cascade for the Synthesis of 1-Pyrrolines: Application to the Synthesis of 2,3-Dihydro-1H-pyrrolo[2,1-a]isoquinolinium Salts

Article abstract of DOI:10.1002/adsc.201501071

Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, PhI(OCOCF₃)₂, resulted in the formation of 1-pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salts has also been described.

Full text of DOI:10.1002/adsc.201501071

FULL PAPERS
DOI: 10.1002/adsc.201501071
A Hofmann Rearrangement–Ring Expansion Cascade for the
Synthesis of 1-Pyrrolines: Application to the Synthesis of 2,3-Di-
hydro-1H-pyrrolo[2,1-a]isoquinolinium Salts
He Huang,a Qinghua Yang,b Qianqian Zhang,a Jie Wu,a,* Yizhen Liu,a
Chuanjun Song,a,* and Junbiao Changa,*
a
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001,
People’s Republic of China
E-mail: changjunbiao@zzu.edu.cn or chjsong@zzu.edu.cn or wujie@zzu.edu.cn
School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, People’s Republic of
b
China
Received: November 22, 2015; Revised: January 22, 2016; Published online: February 19, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501071.
Abstract: Treatment of cyclobutanecarboxamide odology to the synthesis of 2,3-dihydro-1H-pyrro-
with
bis(trifluoroacetoxy)iodobenzene,
PhI(O- lo[2,1-a]isoquinolinium salts has also been described.
COCF3)2, resulted in the formation of 1-pyrroline via
Hofmann rearrangement of the former followed by Keywords: 1-pyrroline; 2,3-dihydro-1H-pyrrolo[2,1-
in situ ring expansion reaction of the cyclobutyla- a]isoquinolinium salt; cascade reaction; cyclobutane-
mine intermediate. Further elaboration of this meth- carboxamide; rearrangement; ring expansion
Introduction
a reactive intermediate would trigger ring expansion
of the cyclobutane ring.
The ring expansion reaction of small and strained
molecules has attracted the interest of organic chem-
ists for decades.[1] However, unlike the ring expansion Results and Discussion
of three-membered rings which have been well stud-
ied and widely applied in natural products synthesis,[2] Initial studies were carried out with 1-phenylcyclobu-
ring expansion reaction of four-membered rings re- tanecarboxamide 1a, which could be easily accessed
mains relatively underutilized.[2d,e,3]
through hydrolysis of 1-phenylcyclobutanecarboni-
The best known ring expansion reaction of cyclobu- trile.[11] As shown in Table 1, treatment of 1a with
tane derivatives was the Wagner–Meerwein-type 1,2-
shift reaction via the generation of a carbenium ion
adjacent to the cyclobutane ring[4–6] or a transition-
Table 1. Results for treatment of 1-phenylcyclobutanecar-
boxamide with bis(trifluoroacetoxy)iodobenzene (BTI).
metal-catalyzed process[7,8] to provide cyclopentane
analogues. Ring expansions with the generation of an
adjacent nitrenium ion to give nitrogen-containing
heterocyclic homologues were rare.[9] Herein, we
report a Hofmann rearrangement–ring expansion cas-
cade of cyclobutanecarboxamides to generate 1-pyrro-
line derivatives, which are key intermediates for the
synthesis of a large variety of functionalized aza-het-
erocycles that exhibit significant biological and phar-
macological activities.[10] It was envisioned that under
the reaction conditions, nucleophilic attack of bis(tri-
fluoroacetoxy)iodobenzene (BTI) with cyclobutyla-
mine (Hofmann rearrangement product) generating
Entry Equiv. of BTI Yield of 2 (%)[a] Yield of 3a (%)[a]
1
2
3
4
5
1
1.5
2
2.5
3
59
25
6
–
–
7
50
81
91
91
[a]
Isolated yield.
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A Hofmann Rearrangement–Ring Expansion Cascade
Table 2. Synthesis of 1-pyrrolines from cyclobutanecarboxa-
1 equivalent of BTI mainly resulted in the formation
of the Hofmann rearrangement product 2 (59% iso-
lated yield, entry 1). The ring expansion product 2-
phenyl-1-pyrroline 3a was isolated only as a minor
product (7%). We then investigated the effects of the
quantities of BTI to the reaction. As can be seen
from Table 1, the yield of 3a improved while that of 2
decreased with increasing amount of BTI (entries 1–
4). In the presence of 2.5 equivalent of BTI, pyrroline
3a was isolated in the highest 91% yield while no
trace of amine 2 was evident on TLC plate (entry 4).
However, no improvement was observed when 3
equivalent of BTI was applied (entry 5). The reaction
conditions were then explored and it was found that
other solvent systems such as DMF, DMF/H2O or
DCM were less satisfactory and the reaction was ide-
ally carried out at ambient temperature.
mides.[a]
Next, we investigated the synthesis of other pyrro-
line derivatives from the corresponding cyclobutane-
carboxamides, and the results are collected in Table 2.
In the presence of 2.5 equivalent of BTI, all 1-arylcy-
clobutanecarboxamides with either an ortho-, meta-,
or para-substituted aromatic ring could react to give
the 2-aryl-1-pyrrolines (entries 2–8). In general, sub-
strates with a strong electron-withdrawing group gave
lower product yield (entries 2–4 vs 5, entry 6 vs 7).
Under the conditions, 3,3-dimethyl-1-phenylyclobuta-
necarboxamide 1i (entry 9) and the dicyclobutanecar-
boxamide 1j (entry 10) could also be converted into
pyrroline 3i and dipyrroline 3j, respectively. The cas-
cade reaction of pyridin-2-ylcyclobutanecarboxamide
1k and pyridin-3-ylcyclobutanecarboxamide 1l were
then explored. While 1l reacted cleanly to give 3l in
83% isolated yield (entry 12), reaction of 1k gave
a mixture of products, from which the desired pyridi-
nylpyrroline 3k was isolated in 35% yield. Following
known literature procedure,[12] 3l could be converted
into the natural product nicotine. Finally, the cascade
reaction of 1-alkylcyclobutanecarboxamides 1m and
1n was also successful and gave the corresponding
pyrrolines 3m and 3n in 84% and 63% isolated
yield, respectively (entries 13, 14).
In a separate study, it was found that 1-phenylcyclo-
butylamine 2 could be converted into 2-phenyl-1-pyr-
roline 3a in 90% isolated yield by treatment with
excess BTI (Scheme 1). Based on the results obtained,
a plausible mechanism was proposed in Scheme 2.
Nucleophilic attack of cyclobutanecarboxamide I to
BTI gave intermediate II, which on rearrangement
Scheme 1. Formation of 2-phenyl-1-pyrroline 3a via ring ex-
pansion of 1-phenylcyclobutylamine 2.
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He Huang et al.
Table 2. (Continued)
in 80% isolated yield. Complete cleavage of C–C
triple bond with hypervalent iodanes to provide the
corresponding carboxylic acids, esters, amides and ke-
toesters have been reported in the literature.[14] To the
best of our knowledge, this example represents the
first non-metallic approach for the cleavage cum func-
tionalization of alkynes to obtain isoquinoline-1,3-
diones. Obviously, alkyne cleavage (possibly with the
aid of the amide functionality) with BTI proceeded
much faster than the Hofmann rearrangement reac-
tion.
Next, we tested the nickel-catalyzed cyclization of
bromophenylpyrroline 3h with alkynes.[15] To our de-
light, the reaction proceeded as expected with termi-
nal alkynes 5a–d (entries 1–4, Table 3) as well as di-
phenylacetylene 5e (entry 5, Table 3) to give the cor-
responding 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolini-
um salts 6a–e in good to excellent isolated yield.
[a]
Reaction conditions: BTI (2.5 equiv), MeCN, H2O, rt.
Isolate yield.
[b]
[c]
5 equivalents of BTI was used.
Table 3. Nickel-catalyzed cyclization of bromophenylpyrro-
line 3h with alkynes for the synthesis of 2,3-dihydro-1H-pyr-
rolo[2,1-a]isoquinolinium salts.
Scheme 2. Proposed mechanism.
yielded isocyanate III. Hydrolysis of III resulted in
the formation of the unstable carbamic acid IV, which
collapsed by losing a molecule of CO2 and simultane-
ously attack BTI to give V. Ring expansion of V gave
carbenium ion VI, and finally deprotonation provided
1-pyrroline VII. Poor result was obtained for the
transformation of 1k to 3k probably because the cor-
responding carbenium ion intermediate (VI, Ar=pyr-
idin-2-yl) was unstable.
Having established the methodology, we then inves-
tigated its utility in chemical synthesis. Hydropyrro-
lo[2,1-a]isoquinoline and analogues exist widely in
nature.[13] We envisioned that these molecules might
be accessed through a Hofmann rearrangement-ring
expansion-cyclization cascade of alkynylphenylcyclo-
butanecarboxamides (e. g., 1o in Scheme 3) in the
presence of BTI. However, treatment of 1o with BTI
resulted in the formation of isoquinoline-1,3-dione 4
[a]
Scheme 3. Synthesis of isoquinoline-1,3-dione 4.
Isolate yield.
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A Hofmann Rearrangement–Ring Expansion Cascade
2.05–1.97 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d=
Conclusions
173.3, 159.6, 135.8, 129.3, 120.4, 116.9, 111.7, 61.4, 55.3, 35.0,
22.6 ppm; HRMS (ESI): m/z calcd for C11H13NO: 176.1070
[M + H]+; found 176.1062.
In summary, we have developed an approach for the
synthesis of 1-pyrrolines via a Hofmann rearrange-
ment–ring expansion cascade of cyclobutanecarboxa-
mides. This approach is well adapted for the nickel-
catalyzed synthesis of 2,3-dihydro-1H-pyrrolo[2,1-
a]isoquinolinium salts.
2-(3’-Trifluoromethylphenyl)-1-pyrroline (3e).[19] Orange
1
oil (181 mg, 85%); H NMR (400 MHz, DMSO): d=8.10 (s,
1H), 8.07 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.67
(t, J=7.8 Hz, 1H), 3.96 (tt, J=7.3, 1.9 Hz, 2H), 2.96–2.92
(m, 2H), 1.99–1.90 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d=172.0, 135.3, 130.9 (q, JFÀC =32.4 Hz), 130.7 (q,
J
FÀC =1.2 Hz), 128.9, 126.7 (q, JFÀC =3.7 Hz), 124.4 (q, JFÀC =
Experimental Section
3.9 Hz), 123.9 (q, JFÀC =271.0 Hz), 61.7, 34.9, 22.7 ppm;
HRMS (ESI): m/z calcd for C11H10F3N: 214.0838 [M + H]+;
found 214.0808.
General
2-(4’-Bromophenyl)-1-pyrroline (3 f).[16] Colorless solid
(202 mg, 90%); mp 79–80 8C [ref. 16, mp 83–84 8C];
1H NMR (400 MHz, CDCl3): d=7.68 (d, J=7.7 Hz, 2H),
7.51 (d, J=7.7 Hz, 2H), 4.03 (m, 2H), 2.88 (m, 2H), 2.06–
1.98 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d=172.3,
133.4, 131.6, 129.1, 124.7, 61.6, 34.8, 22.7 ppm; HRMS (ESI):
m/z calcd for C10H10BrN: 224.0069 [M + H]+; found
224.0063.
Melting points were determined on a XT4A hot-stage appa-
ratus and are uncorrected. IR spectra were obtained using
an IFS25 FT-IR spectrometer. 1H and 13C NMR spectra
were obtained on a Agilent AV400 instrument. High-resolu-
tion mass spectra were recorded on a Micromass Q-TOF
mass spectrometer.
2-(4’-Nitrophenyl)-1-pyrroline (3g).[20] Colorless solid
(156 mg, 82%); mp 140–141 8C; 1H NMR (400 MHz,
CDCl3): d=8.26–8.23 (m, 2H), 8.00–7.97 (m, 2H), 4.10 (tt,
J=7.5, 2.2 Hz, 2H), 2.99–2.94 (m, 2H), 2.13–2.05 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d=171.6, 148.8, 140.2,
128.4, 123.6, 62.0, 35.1, 22.7 ppm; HRMS (ESI): m/z calcd
for C10H10N2O2: 191.0815 [M ++ H]+; found 191.0815.
2-(2’-Bromophenyl)-1-pyrroline (3h).[21] Orange oil
(143 mg, 64%); 1H NMR (400 MHz, CDCl3): d=7.56 (dd,
J=8.0, 1.0 Hz, 1H), 7.42 (dd, J=7.6, 1.6 Hz, 1H), 7.30 (td,
J=7.5, 1.0 Hz, 1H), 7.20 (td, J=7.7, 1.6 Hz, 1H), 4.01 (tt,
J=7.5, 2.0 Hz, 2H), 2.96 (tt, J=8.5, 2.0 Hz, 2H), 2.07–2.00
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d=175.3, 137.7,
133.2, 130.3, 130.0, 127.2, 121.0, 61.4, 38.5, 23.4 ppm; HRMS
(ESI): m/z calcd for C10H10BrN: 226.0049 [M + H]+; found
226.0037.
General procedure for the synthesis of 3a–n
To
a
solution of 1-arylcyclobutanecarboxamide 1a–n
(1.0 mmol, 1.0 equiv) in acetonitrile (6 mL) and water
(2 mL) was added bis(trifluoroacetoxy)iodobenzene (BTI,
2.5 mmol, 2.5 equiv). The resulting mixture was stirred at
ambient temperature for 12 h before being slowly poured
into saturated K2CO3 solution (10 mL). The resulting mix-
ture was extracted with ethyl acetate (20 mL ” 3). The com-
bined organic extracts were washed with brine, then dried
over Na2SO4, filtered, and evaporated in vacuo. The residue
was purified by column chromatography on silica gel to give
2-aryl-1-pyrroline 3a–n.
2-Phenyl-1-pyrroline (3a).[16] Orange oil (132 mg, 91%);
1H NMR (400 MHz, CDCl3): d=7.87–7.81 (m, 2H), 7.44–
7.37 (m, 3H), 4.05 (tt, J=7.5, 2.0 Hz, 2H), 2.97–2.92 (m,
2H), 2.07–1.99 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d=173.3, 134.5, 130.3, 128.4, 127.6, 61.4, 34.9, 22.6 ppm;
HRMS (ESI): m/z calcd for C10H11N: 146.0964 [M + H]+;
found 146.0949.
2-Phenyl-4,4-dimethyl-1-pyrroline (3i).[22] Colorless oil
(152 mg, 88%); 1H NMR (400 MHz, CDCl3): d=7.80–7.78
(m, 2H), 7.41–7.38 (m, 3H), 3.79 (s, 2H), 2.77 (s, 2H), 1.17
(s, 6H) ppm; 13C NMR (100 MHz, CDCl3): d=173.0, 134.8,
130.3, 128.4, 127.4, 74.6, 49.9, 38.4, 28.1 ppm; HRMS (ESI):
m/z calcd for C12H15N: 174.1277 [M + H]+; found 174.1259.
1,3-Bis(1’-pyrrolin-2’-yl)benzene (3j). The title compound
was obtained by treatment of 1j with 5 equivalent of BTI.
Colorless solid (170 mg, 80%); mp 127–128 8C; IR (KBr):
2-(3’-Chlorophenyl)-1-pyrroline (3b).[17] Colorless solid
(163 mg, 91%); mp 47–48 8C [ref. 17, mp 54 8C]; H NMR
1
(400 MHz, CDCl3): d=7.81 (d, J=1.6 Hz, 1H), 7.68 (d, J=
7.6 Hz, 1H), 7.38–7.29 (m, 2H), 4.07–4.03 (m, 2H), 2.92–
2.86 (m, 2H), 2.06–1.98 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d=172.3, 136.2, 134.5, 130.3, 129.7, 127.7, 125.7,
61.5, 35.0, 22.6 ppm; HRMS (ESI): m/z calcd for C10H10ClN:
180.0575 [M + H]+; found 180.0576.
nmax =1620, 1575, 1443, 1321, 1264, 1198 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=8.22 (t, J=1.4 Hz,1H), 7.91 (dd, J=
7.7, 1.4 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 4.08–4.03 (m, 4H),
2.99–2.94 (m, 4H), 2.06–1.98 (m, 4H) ppm; 13C NMR
(100 MHz, CDCl3): d=173.1, 134.7, 129.4, 128.6, 126.9, 61.6,
35.0, 22.7 ppm; HRMS (ESI): m/z calcd for C14H16N2:
213.1386 [M + H]+; found 213.1374.
2-(3’-Bromophenyl)-1-pyrroline (3c).[17] Yellow solid
(202 mg, 90%); mp 42–43 8C [ref. 17, mp 49–508C];
1H NMR (400 MHz, CDCl3): d=7.97 (s, 1H), 7.72 (d, J=
8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz,
1H), 4.04 (t, J=7.3 Hz, 2H), 2.94–2.89 (m, 2H), 2.08–2.00
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d=172.1, 136.5,
133.1, 130.6, 129.9, 126.1, 122.6, 61.5, 34.9, 22.6 ppm; HRMS
(ESI): m/z calcd for C10H10BrN: 224.0069 [M + H]+; found
224.0066.
2-(2’-Pyridyl)-1-pyrroline (3k).[23] Colorless solid (51 mg,
35%); mp 41–42 8C [ref. 23, mp 44–46 8C]; 1H NMR
(400 MHz, CDCl3): d=8.62 (d, J=4.8 Hz, 1H), 8.09 (d, J=
8.0 Hz, 1H), 7.74–7.69 (m, 1H), 7.31–7.28 (m, 1H), 4.09 (tt,
J=7.3, 2.1 Hz, 2H), 3.11–3.06 (m, 2H), 2.06–1.98 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d=175.1, 153.3, 149.0,
136.3, 124.5, 121.8, 62.1, 34.9, 22.5 ppm; HRMS (ESI): m/z
calcd for C9H10N2: 147.0917 [M + H]+; found 147.0913.
2-(3’-Methoxyphenyl)-1-pyrroline (3d).[18] Orange oil
(166 mg, 95%); 1H NMR (400 MHz, CDCl3): d=7.42 (m,
1H), 7.35–7.27 (m, 2H), 6.94 (ddd, J=8.0, 2.6, 1.1 Hz, 1H),
4.03 (tt, J=7.5, 2.0 Hz, 2H), 3.81 (s, 3H), 2.94–2.89 (m, 2H),
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He Huang et al.
2-(3’-Pyridyl)-1-pyrroline (3l).[24] Colorless solid (121 mg,
yield 83%); mp 34–35 8C; H NMR (400 MHz, CDCl3): d=
5-Phenyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolin-4-ium
bromide (6a).Colorless solid (245 mg, 75%); mp 236–237
1
8.98 (m, 1H), 8.64 (m, 1H), 8.18 (m, 1H), 7.34 (m, 1H),
4.07 (m, 2H), 2.95 (m, 2H), 2.06 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d=171.0, 151.1, 149.0, 134.7, 130.2,
123.4, 61.6, 34.8, 22.5 ppm; HRMS (ESI): m/z calcd for
C9H10N2: 147.0917 [M + H]+; found 147.0920.
8C; IR (KBr): nmax =2998, 1634, 1567, 1497, 1454, 1348 cmÀ1
;
1H NMR (400 MHz, CD3OD): d=8.51 (dd, J=8.3, 1.2 Hz,
1H), 8.31 (d, J=8.3 Hz, 1H), 8.27 (s, 1H), 8.21 (ddd, J=8.3,
7.0, 1.2 Hz, 1H), 8.06 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.76–
7.73 (m, 2H), 7.68–7.64 (m, 3H), 4.83 (t, J=7.8 Hz, 2H),
4.15 (t, J=7.8 Hz, 2H), 2.66–2.58 (m, 2H) ppm; 13C NMR
(100 MHz, CD3OD): d=165.1, 145.1, 139.5, 137.6, 133.9,
132.2, 131.8, 130.6, 130.3, 129.6, 129.2, 126.3, 125.5, 60.8,
33.6, 21.8 ppm; HRMS (ESI): m/z calcd for C18H16N:
246.1277; found 246.1280.
5-Benzyl-1-pyrroline (3m).[25] Colorless oil (134 mg, yield
1
84%); H NMR (400 MHz, CDCl3): d=7.32–7.28 (m, 2H),
7.24–7.20 (m, 3H), 3.85–3.80 (m, 2H), 3.67 (s, 2H), 2.41–
2.37 (m, 2H), 1.86–1.78 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d=176.9, 137.1, 129.1, 128.7, 126.7, 61.0, 40.8, 36.6,
22.7 ppm; HRMS (ESI): m/z calcd for C11H13N: 160.1121 [M
+ H]+; found 160.1133.
5-(p-Tolyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolin-4-
ium bromide (6b). Colorless solid (262 mg, 77%); mp 250–
251 8C; IR (KBr): nmax =2922, 1632, 1565, 1508, 1434, 1377,
5-(3-Phenylpropyl)-1-pyrroline
(118 mg, yield 63%); IR (NaCl): nmax =2942, 2863, 1643,
1603, 1496, 1453 cmÀ1 1H NMR (400 MHz, CDCl3): d=
(3n).
Colorless
oil
1341 cmÀ1 1H NMR (400 MHz, CD3OD): d=8.49 (d, J=
;
;
8.4 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.23 (s, 1H), 8.21–8.17
(m, 1H), 8.06–8.02 (m, 1H), 7.62 (d, J=7.9 Hz, 2H), 7.47
(d, J=7.9 Hz, 2H), 4.82 (t, J=7.7 Hz, 2H), 4.12 (t, J=
7.9 Hz, 2H), 2.65–2.57 (m, 2H), 2.49 (s, 3H) ppm; 13C NMR
(100 MHz, CD3OD): d=165.0, 145.3, 142.4, 139.6, 137.5,
132.0, 131.0, 130.9, 130.5, 129.5, 129.1, 126.2, 125.5, 125.4,
60.8, 33.6, 21.9, 21.5 ppm; HRMS (ESI): m/z calcd for
C19H18N: 260.1434; found 260.1440.
7.29–7.25 (m, 2H), 7.19–7.15 (m, 3H), 3.82–3.77 (m, 2H),
2.66 (t, J=2.7 Hz, 2H), 2.45–2.40 (m, 2H), 2.37–2.33 (m,
2H), 1.98–1.90 (m, 2H), 1.87–1.79 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d=178.1, 142.0, 128.6, 128.4, 125.9, 60.9,
37.3, 35.7, 33.3, 28.0, 22.6 ppm; HRMS (ESI): m/z calcd for
C13H17N: 188.1434 [M + H]+; found 188.1434.
5-(4-Chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoqui-
nolin-4-ium bromide (6c). Colorless solid (260 mg, 72%);
mp 193–194 8C; IR (KBr): nmax =2924, 1638, 1572, 1496,
1’H-spiro[cyclobutane-1,4’-isoquinoline]-1’,3’(2’H)-
dione (4)
1
1464, 1376 cmÀ1; H NMR (400 MHz, CD3OD): d=8.50 (d,
To a solution of 1-[2’-(phenylethynyl)phenyl]cyclobutane-1-
carboxamide (275 mg, 1.0 mmol, 1.0 equiv) in acetonitrile
(10 mL) and water (4 mL) was added BTI (1075 mg,
2.5 mmol, 2.5 equiv). The resulting mixture was stirred at
ambient temperature for 12 h before being slowly poured
into 10% aqueous NaOH (10 mL). The resulting mixture
was extracted with ethyl acetate (20 mL ” 3). The combined
organic extracts were washed with brine, then dried over
Na2SO4, filtered, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel with 25%
ethyl acetate in petroleum ether as eluent to give 1’H-spiro[-
J=8.4 Hz, 1H), 8.31–8.28 (m, 2H), 8.23–8.19 (m, 1H), 8.06–
8.04 (m, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz,
2H), 4.81 (t, J=7.7 Hz, 2H), 4.13 (t, J=7.9 Hz, 2H), 2.62
(m, 2H) ppm; 13C NMR (100 MHz, CD3OD): d=165.4,
143.9, 139.5, 138.2, 137.7, 132.4, 132.3, 130.5, 129.6, 129.2,
126.6, 125.6, 60.8, 33.6, 21.8 ppm; HRMS (ESI): m/z calcd
for C18H15ClN: 280.0888; found 280.0890.
5-(4-(Trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrolo[2,1-
a]isoquinolin-4-ium bromide (6d). Colorless solid (355 mg,
90%); mp 248–249 8C; IR (KBr): nmax =2925, 1634, 1570,
1466, 1437, 1323 cmÀ1 1H NMR (400 MHz, CD3OD): d=
;
cyclobutane-1,4’-isoquinoline]-1’,3’(2’H)-dione
4
(161 mg,
8.53 (d, J=8.4 Hz, 1H), 8.34–8.32 (m, 2H), 8.25–8.21 (m,
1H), 8.11–8.06 (m, 1H), 8.00–7.96 (m, 4H), 4.83 (t, J=
7.6 Hz, 2H), 4.16 (t, J=7.9 Hz, 2H), 2.67–2.60 (m, 2H)
ppm; 13C NMR (100 MHz, CD3OD): d=164.3, 142.0, 138.0,
136.4, 136.2, 132.2 (q, JFÀC =32.7 Hz), 131.1, 130.4, 128.4,
80%) as a colorless solid; mp 156–157 8C; 1H NMR
(400 MHz, CDCl3): d=8.84 (s, 1H), 8.19 (dd, J=7.9, 1.2 Hz,
1H), 7.84 (d, J=7.6 Hz, 1H), 7.76–7.72 (m, 1H), 7.47–7.43
(m, 1H), 3.01–2.94 (m, 2H), 2.50–2.39 (m, 3H), 2.35–2.22
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3): d=176.7, 164.6,
145.1, 134.9, 128.4, 127.5, 125.7, 123.6, 47.1, 34.8, 15.7 ppm;
HRMS (ESI): m/z calcd for C12H11NO2: 202.0863 [M + H]+;
found 202.0863.
127.9, 125.8 (q, JFÀC =3.8 Hz), 125.4, 124.4, 123.9 (q, JFÀC
=
271.8 Hz), 59.5, 32.3, 20.5 ppm; HRMS (ESI): m/z calcd for
C19H15F3N: 314.1151; found 314.1152.
5,6-Diphenyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolin-4-
ium bromide (6e). Colorless solid (342 mg, 85%); mp 214–
215 8C; IR (KBr): nmax =2924, 1622, 1590, 1461, 1443,
General procedure for the synthesis of 6a–e
1
1379 cmÀ1; H NMR (400 MHz, CD3OD): d=8.58–8.56 (m,
A seal tube (35 mL) containing Ni(PPh3)2Br2 (0.05 mmol,
0.05 equiv), Zn (0.5 mmol, 0.5 equiv) and 2-(2’-bromophen-
yl)-1-pyrroline 3h (1.0 mmol, 1.0 equiv) was evacuated and
purged with nitrogen gas three times. Freshly distilled THF
(5.0 mL) and alkyne 5a–e (1.0 mmol, 1.0 equiv) were added
to the system. The resulting mixture was stirred at 80 8C for
10 h. The mixture was diluted with dichloromethane
(15 mL), filtered through a pad of celite and silica gel and
washed with methanol (50 mL). The filtrate was concentrat-
ed, and the residue was purified by column chromatography
on silica gel with dichloromethane/methanol as eluent to
give 2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salt 6a–e.
1H), 8.12–8.04 (m, 2H), 7.75–7.73 (m, 1H), 7.45–7.39 (m,
5H), 7.38–7.34 (m, 3H), 7.29–7.24 (m, 2H), 4.65–4.61 (m,
2H), 4.20 (t, J=7.9 Hz, 2H), 2.65–2.61 (m, 2H) ppm;
13C NMR (100 MHz, CD3OD): d=163.8, 143.0, 139.3, 138.4,
137.5, 134.8, 133.1, 132.0, 131.7, 131.2, 131.1, 129.9, 129.8,
129.7, 129.5, 128.1, 125.7, 61.7, 33.8, 21.3 ppm; HRMS (ESI):
m/z calcd for C24H20N: 322.1590; found 322.1593.
1134
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1130 – 1135

FULL PAPERS
A Hofmann Rearrangement–Ring Expansion Cascade
j) S. G. Sethofer, S. T. Staben, O. Y. Hung, F. D. Toste,
Acknowledgements
Org. Lett. 2008, 10, 4315–4318; k) H. Nemoto, M. Yosh-
ida, K. Fukumoto, J. Org. Chem. 1997, 62, 6450–6451.
[8] a) K.-D. Kim, H.-S. Yeom, S. Shin, S. Shin, Tetrahedron
2012, 68, 5241–5247; b) R. C. Larock, C. K. Reddy, Org.
Lett. 2000, 2, 3325–3327; c) R. C. Larock, C. K. Reddy,
J. Org. Chem. 2002, 67, 2027–2033; d) J. P. Markham,
S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
9708–9709; e) L. S. Liebeskind, A. Bombrun, J. Org.
Chem. 1994, 59, 1149–1159; f) Y. Yamamoto, M. Ohno,
S. Eguchi, Tetrahedron Lett. 1995, 36, 5539–5542; g) M.
Ohno, Y. Yamamoto, S. Eguchi, Synlett 1998, 1167–
1174; h) H. Yin, S. W. Dantale, N. G. Akhmedov,
B. C. G. Sçderberg, Tetrahedron 2013, 69, 9284–9293.
[9] a) P. Kovacic, M. K. Lowery, P. D. Roskos, Tetrahedron
1970, 26, 529–538; b) P. G. Gassman, A. Carrasquillo,
Tetrahedron Lett. 1971, 12, 109–112.
We are grateful to the NSFC (#81330075; #21172202;
#21201152) and Zhengzhou University (#1421316040) for fi-
nancial support.
References
[1] M. Hesse, Ring Enlargement in Organic Chemistry,
VCH, 1991.
[2] For selected reviews, see: a) J. T. Njardarson, Synlett
2013, 787–803; b) E. A. Ilardi, J. T. Njardarson, J. Org.
Chem. 2013, 78, 9533–9540; c) Y. M. Heo, S.-M. Paek,
Molecules 2013, 18, 9650–9662; d) D. J. Mack, J. T.
Njardarson, ACS Catal. 2013, 3, 272–286; e) D. Ga-
rayalde, C. Nevado, Beilstein J. Org. Chem. 2011, 7,
767–780.
[3] For selected reviews, see: a) J. C. Namyslo, D. E. Kauf-
mann, Chem. Rev. 2003, 103, 1485–1537; b) T. Seiser, T.
Saget, D. N. Tran, N. Cramer, Angew. Chem. 2011, 123,
7884–7896; Angew. Chem. Int. Ed. 2011, 50, 7740–7752.
[4] a) D. C. Moebius, J. S. Kingsbury, J. Am. Chem. Soc.
2009, 131, 878–879; b) J. A. Dabrowski, D. C. Moebius,
A. J. Wommack, A. F. Kornahrens, J. S. Kingsbury, Org.
Lett. 2010, 12, 3598–3601; c) L. M. Reeder, L. S. Hege-
dus, J. Org. Chem. 1999, 64, 3306–3311; d) A. E.
Greene, M. J. Luche, A. A. Serra, J. Org. Chem. 1985,
50, 3957–3962; e) G. Mehta, M. S. Nair, J. Am. Chem.
Soc. 1985, 107, 7519–7524.
[5] a) L. A. Paquette, D. R. Owen, R. T. Bibart, C. K. See-
kamp, A. L. Kahane, J. C. Lanter, M. A. Corral, J. Org.
Chem. 2001, 66, 2828–2834; b) L. A. Paquette, M. J.
Kinney, U. Dullweber, J. Org. Chem. 1997, 62, 1713–
1722; c) Q. W. Zhang, C. A. Fan, H. J. Zhang, Y. Q. Tu,
Y. M. Zhao, P. Gu, Z. M. Chen, Angew. Chem. 2009,
121, 8724–8726; Angew. Chem. Int. Ed. 2009, 48, 8572–
8574; d) E. Zhang, C. A. Fan, Y. Q. Tu, F. M. Zhang,
Y. L. Song, J. Am. Chem. Soc. 2009, 131, 14626–14627;
e) T. Cohen, L. C. Yu, W. M. Daniewski, J. Org. Chem.
1985, 50, 4596–4600; f) B. M. Trost, D. W. C. Chen, J.
Am. Chem. Soc. 1996, 118, 12541–12554.
[10] B. E. Maryanoff, D. F. McComsey, J. F. Gardocki, R. P.
Shank, M. J. Costanzo, S. O. Nortey, C. R. Schneider,
P. E. Setler, J. Med. Chem. 1987, 30, 1433–1454.
´
[11] M. Barbasiewicz, K. Marciniak, M. Fedorynski, Tetra-
hedron Lett. 2006, 47, 3871–3874.
[12] H. Brunner, A. Kürzinger, S. Mahboobi, W. Wiegrebe,
Arch. Pharm. 1988, 321, 73–76.
[13] a) Q. Zhang, G. Tu, Y. Zhao, T. Cheng, Tetrahedron
2002, 58, 6795–6798; b) R. F. Wang, X. W. Yang, C. M.
Ma, S. Q. Cai, J. J. Nong, Y. Shoyama, Heterocycles
2004, 63, 1443–1448; c) L. Xiang, D. Xing, W. Wang, R.
Wang, Y. Ding, L. Du, Phytochemistry 2005, 66, 2595–
2601; d) J. Ewing, G. K. Hughes, E. Ritchie, W. C.
Taylor, Nature 1952, 169, 618–619; e) A. I. Meyers,
T. M. Sielecki, J. Am. Chem. Soc. 1991, 113, 2789–2790.
[14] S. Khamarui, R. Maiti, D. K. Maiti, Chem. Commun.
2015, 51, 384–387 and references therein.
[15] W.-C. Shih, C.-C. Teng, K. Parthasarathy, C.-H. Cheng,
Chem. Asian J. 2012, 7, 306–313.
[16] P. N. D. Singh, R. F. Klima, S. Muthukrishnan, R. S.
Murthy, J. Sankaranarayanan, H. M. Stahlecker, B.
Patel, A. D. Gudmundsdóttir, Tetrahedron Lett. 2005,
46, 4213–4217.
[17] C. Coindet, A. Comel, G. Kirsch, Tetrahedron Lett.
2001, 42, 6101–6104.
[18] F. Chen, Z. Ding, J. Qin, T. Wang, Y. He, Q. Fan, Org.
Lett. 2011, 13, 4348–4351.
[19] N. E. Shevchenko, K. Vlasov, V. G. Nenajdenko, G.
Rçeschenthaler, Tetrahedron 2011, 67, 69–74.
[20] F. Foschi, D. Landini, V. Lupi, V. Mihali, M. Penso, T.
Pilati, A. Tagliabue, Chem. Eur. J. 2010, 16, 10667–
10670.
[21] B. E. Maryanoff, J. L. Vaught, R. P. Shank, D. F.
McComsey, M. J. Costanzo, S. O. Nortey, J. Med. Chem.
1990, 33, 2793–2797.
[22] A. G. J. Anderson, M. T. Wills, J. Org. Chem. 1967, 32,
3241–3243.
[23] A. Giovannini, D. Savoia, A. Umani-Ronchi, J. Org.
Chem. 1989, 54, 228–234.
[24] B. Sezen, D. Sames, J. Am. Chem. Soc. 2004, 126,
13244–13246.
[25] H. Kim, T. Livinghouse, P. H. Lee, Tetrahedron 2008,
64, 2525–2529.
[6] a) L. Fitjer, M. Majewski, A. Kanschik, E. Egert, G. M.
Sheldrick, Tetrahedron Lett. 1986, 27, 3603–3606;
b) Jahangir, L. E. Fisher, R. D. Clark, J. M. Muchowski,
J. Org. Chem. 1989, 54, 2992–2996; c) H. Brunner,
H. B. Kagan, G. Kreutzer, Tetrahedron: Asymmetry
2001, 12, 497–499.
[7] a) B. M. Trost, J. Xie, J. Am. Chem. Soc. 2006, 128,
6044–6045; b) B. M. Trost, J. Xie, J. Am. Chem. Soc.
2008, 130, 6231–6242; c) B. M. Trost, T. Yasukata, J.
Am. Chem. Soc. 2001, 123, 7162–7163; d) Z. Chai, T. J.
Rainey, J. Am. Chem. Soc. 2012, 134, 3615–3618; e) A.
Schweinitz, A. Chtchemelinine, A. Orellana, Org. Lett.
2011, 13, 232–235; f) H. Nemoto, M. Nagamochi, H.
Ishibashi, K. Fukumoto, J. Org. Chem. 1994, 59, 74–79;
g) H. Nemoto, M. Shiraki, K. Fukumoto, Synlett 1994,
599–600; h) L. E. Overman, M. E. Okazaki, E. J. Jacob-
sen, J. Org. Chem. 1985, 50, 2403–2405; i) G. R. Clark,
S. Thiensathit, Tetrahedron Lett. 1985, 26, 2503–2506;
Adv. Synth. Catal. 2016, 358, 1130 – 1135
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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