An unexpected Bromolactamization of Olefinic Amides Using a Three-Component Co-catalyst System

Article abstract of DOI:10.1021/acs.joc.5b02390

Reaction between (N,N-dimethylamino)pyridine and isocyanate unexpectedly produced a three-component mixture. By using this mixture as an unprecedented three-component catalyst system, a facile and selective bromolactamization of olefinic amides has been developed. The protocol confers enhanced selectivity of N- over O-cyclization, leading to the formation of a structurally diverse range of lactams including both small and medium ring sizes.

Full text of DOI:10.1021/acs.joc.5b02390

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Article
An Unexpected Bromolactamization of Olefinic
Amides Using a Three-Component Co-catalyst System
Yi An Cheng, Wesley Zongrong Yu, and Ying-Yeung Yeung
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02390 • Publication Date (Web): 17 Dec 2015
Downloaded from http://pubs.acs.org on December 19, 2015
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An Unexpected Bromolactamization of Olefinic Amides Using a
Three-Component Co-catalyst System
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Yi An Cheng,2 Wesley Zongrong Yu2 and Ying-Yeung Yeung1,2,
*
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1 Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong,
China
2 3 Science Drive 3, Department of Chemistry, National University of Singapore, Singapore
117543
Email: yyyeung@cuhk.edu.hk
Abstract: Reaction between N,Nꢀdimethylaminopyridine and isocyanate unexpectedly
produced a threeꢀcomponent mixture. By using this mixture as an unprecedented threeꢀ
component catalyst system, a facile and selective bromolactamization of olefinic amides has
been developed. The protocol confers enhanced selectivity of Nꢀ over Oꢀcyclization, leading
to the formation of a structurally diverse range of lactams including both small and mediumꢀ
ring sizes.
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INTRODUCTION
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Electrophilic reactions, such as halolactonization, have been the subject of intensive
research interest.1 In recent years, elegant reports on haloaminocyclization reactions have
been documented.2 In haloaminocyclization, olefinic amines, which contain a single nitrogen
nucleophile, could undergo ringꢀclosing in the presence of an electrophilic halogen source to
afford Nꢀheterocyclic products, i.e. pyrrolidines and piperidines. The cyclization of an
unactivated olefinic amide, on the other hand, presents formidable challenges. As an olefinic
amide contains both oxygen (hard) and nitrogen (soft) nucleophiles in the same system, a key
issue is the difficulty to induce Nꢀcyclization to give the desired lactam based on the
Hard/Soft AcidꢀBase Theory (HSAB).3 Due to the higher electronegativity of oxygen
compared to nitrogen in an amide system, Oꢀcyclization commonly occurs as the
predominant pathway in the halocyclization of olefinic amide substrates and consequently
there is very little or no Nꢀcyclization. In many cases, hydrolysis of the Oꢀcyclized products
could furnish the corresponding lactones and this has commonly been employed as a strategy
for preparing lactones in various multistep syntheses.4
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Scheme 1. Various Strategies to Achieve N-Cyclization.
As lactams are prevalent in a variety of natural products and pharmaceuticals,5
concise and efficient methods to construct lactams will thus be highly valuable from a
synthetic viewpoint. Sporadic reports of protocols for electrophilic halocyclization that gave
small ring (e.g. 5ꢀ and 6ꢀmembered) Nꢀcyclized products have been documented (Scheme 1).
For examples, some cyclizations can be promoted by stoichiometric amounts of alkali metal
base6. In a report of iodocyclization of N,Oꢀbis(trimethylsilyl) derivatives, fiveꢀmembered
ring iodolactams can be obtained in good yields but two equivalents of moisture sensitive
TMSOTf are required.7 In many cases, highly specific substrates such as olefinic carbamates
or ureas were used to achieve the desired Nꢀcyclization.8 Conversely, a general protocol that
can effect the direct cyclization of an olefinic amide to give the lactam remains largely
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elusive. Recently, we reported a carbamateꢀcatalyzed enantioselective bromolactamization
process.9 Building on our recent research effort, we envisage that the development of a more
general halolactamization reaction that: 1) uses readily available catalysts and reagents and 2)
encompasses a broader and more structurally diverse range of substrates would greatly
enhance its utility in synthetic chemistry. In addition, there is no reported case on the
synthesis of mediumꢀring size lactams through a catalytic halolactamization process.10 Herein
we disclose an unexpected result of the use of a threeꢀcomponent catalyst system in the
lactamization (Nꢀcyclization) of olefinic amides that addresses these gaps in the current
literature. While most coꢀcatalyst systems involving two catalytic species have been
studied,11 this report will demonstrate a highly uncommon cooperative organocatalytic
protocol using three catalytic species.
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RESULTS AND DISCUSSION
Previously, we described the use of the sulfurꢀbased zwitterionic catalyst 1 in the
mediumꢀring lactonization reaction of olefinic acids.12 The sulfur catalyst 1 could be obtained
by the reaction between N,Nꢀdimethylaminopyridine (DMAP, 2) and aryl isothiocyanate 3
(Scheme 2, eq 1). Our more recent experiments to obtain the analogous oxygen zwitterion
(i.e. the putative zwitterion “5”) for the halocyclization, however, have led to an intriguing
discovery. When DMAP (2) was reacted with 3,5ꢀbistrifluoromethylphenyl isocyanate (4), a
white solid was obtained. Detailed physical analysis revealed that this white solid was not the
putative zwitterion “5” (Scheme 2, eq. 2), but unexpectedly consisted of three components:
DMAP
(2),
N,N’ꢀbis[3,5ꢀ(bistrifluoromethyl)phenyl]urea
(6),
and
3,5ꢀ
(bistrifluoromethyl)aniline (7) in 3:1:1 ratio (Scheme 2, eq 3). When the individual
1
components were mixed according to the 3:1:1 ratio, the same H NMR spectra could be
obtained as that of the white solid. On the basis of the ratio, we speculated that the three
components were furnished as
a
result of the rapid hydrolysis of 3,5ꢀ
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bis(trifluoromethyl)phenyl isocyanate (4) by moisture13 to yield the corresponding carbamic
acid followed by decarboxylation which gives aniline 7. Nucleophilic attack of aniline 7 to
another molecule of isocyanate 4 could then yield urea 6. It is worth mentioning that in the
absence of DMAP (2), the hydrolysis of 4 to give 7 was sluggish.
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Scheme 2. Synthesis of Catalysts and Proposed Origin of 6 and 7.
More surprisingly, it was realized that the unexpected threeꢀcomponent mixture could
catalyze the bromolactamization of olefinic amides. The initial model reaction was performed
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using olefinic amide 8a as the substrate and Nꢀbromosuccinimide (NBS) as the stoichiometric
halogen source. 8a contains an electronꢀwithdrawing pꢀtoluenesulfonyl group which
increases the acidity of the amide proton and therefore might aid in Nꢀcyclization. The Nꢀ
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cyclization and Oꢀcyclization selectivity was examined using H NMR. Initially, we tested
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several literature reported protocols that could promote Nꢀcyclization. Sodium hydrogen
carbonate and triethylamine, which could be used to induce Nꢀcyclization of alkenyl urea
systems,8f as well as N,N’ꢀbis[3,5ꢀ(bistrifluoromethyl)phenyl]thiourea (10),14 were ineffective
in promoting the desired Nꢀcyclization of 8a (Table 1, entries 1–4). Notably, the reaction was
also inert towards CuBr2, a promoter used in bromoaminocyclizations2f (entry 5) and a
combination of Pd(OAc)2/CuBr2 (entry 6), that had been used in the bromoꢀNꢀcyclization of
olefinic carbamates.8a,8b In the presence of zwitterionic catalyst 1, a moderate N/Oꢀselectivity
was obtained (Table 1, entry 7). When the white solid (2/6/7, 3:1:1) was employed as a
catalyst (5 mol%) to the reaction, the selectivity was further enhanced to 1:0.4 in favour of
the formation of lactam (Table 1, entry 8) in a short reaction time of 30 min. Interestingly, no
reaction was observed when Nꢀchlorosuccinimide (NCS) was used while Nꢀiodosuccinimide
(NIS) resulted in poorer selectivity (Table 1, entries 9 and 10).
Table 1. Catalyst Screening of the Bromolactamization of Substrate Amide 8aa
O
N
Ts
O
Catalyst/ promoter
NHTs
N
Ts
+
O
NBS, CH2Cl2
40 °C
Br
Br
8a
9a
9a'
Entry
Catalyst/ promoter (loading)
NaHCO3 (1.6 eq)
Et3N (5 mol%)
Time (h)
0.5
0.5
0.5
0.5
Ratio of 9a:9a’b
1:10.0
NR
NR
1
2
3
4
Et3N (1.6 eq)
10, S=C[NH(3,5ꢀCF3ꢀC6H3)]2 (5
9a’ only
mol%)
5c
6d
7
CuBr2 (1.0 eq)
24
24
0.5
NR
NR
1:0.74
Pd(OAc)2 (10 mol%)
1 (5 mol%)
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White solid (2/6/7, 3:1:1) (5 mol%)
White solid (2/6/7, 3:1:1) (5 mol%)
White solid (2/6/7, 3:1:1) (5 mol%)
0.5
0.5
0.5
1:0.4
NR
1:1.1
8
9e
10f
a
Reactions were carried out with olefinic amide 8a (0.3 mmol), catalyst and NBS (0.45 mmol) in CH2Cl2 (6
b
1
mL) at 40 °C in the absence of light. Determined by H NMR analysis on the crude product mixture with
c
internal standard. Unless stated otherwise, full consumption of 8a was achieved. MeCN (6 mL) was used as
the solvent. d Reaction was carried out with 8a (0.3 mmol), Pd(OAc)2 (0.03 mmol), CuBr2 (1.5 mmol) and
K2CO3 (0.6 mmol) in THF (3 mL) at 25 °C in the absence of light. e NꢀChlorosuccinimide was used as the
halogen source. f NꢀIodosuccinimide was used as the halogen source. NR = No reaction.
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Further experiments demonstrated that the presence of all three components is critical
in the catalysis. The Nꢀselectivities dropped dramatically when one or two components were
removed from the catalyst system.15 When 2, 6 and 7 were individually mixed in a 3:1:1 ratio
and used as a reconstituted catalyst system in place of the white solid in the
bromolactamization of 8a, the same N/Oꢀcyclization ratio could be obtained.16
With this promising result, we next directed our efforts towards the synthesis of
pharmaceutically important moieties based on the 1,2,3,4ꢀtetrahydroisoquinoline and indole
scaffolds (Scheme 3).17 The synthesis of these scaffolds usually requires laborious multiꢀstep
sequences. Nonetheless, cyclization of 8b under the optimized conditions gave 1ꢀoxoꢀ1,2,3,4ꢀ
tetrahydroisoquinoline 9b in 84% yield in just 15 minutes. The tetrahydroisoquinoline core
of 9b is featured in both the highly selective phenylethanolamine Nꢀmethyltransferase
(PNMT) inhibitor I18 and the serotonin (5ꢀHT2c) receptor agonist II19. In addition, the
skeleton of III (a conformationallyꢀrigid and potent histamine H3 inverse agonist which is
derived from Pitolisant and GSK 189254)20 could readily be furnished through the cyclization
of 8c, affording 9c in 92% yield in an equally quick reaction time. In stark contrast, very little
or no Nꢀcyclized products 9b and 9c were formed, and significant amounts of Oꢀcyclized
products were obtained instead when N,N’ꢀbis[3,5ꢀ(bistrifluoromethyl)ꢀphenyl]thiourea, or
Lewis acids BF3ꢀTHF and SnCl4 were used as catalysts. These observations further attest to
the enhanced Nꢀ over Oꢀcyclization selectivity with this novel catalytic protocol. The
structures of 9b and 9c were confirmed by Xꢀray crystallographic studies.15
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Scheme 3. Cyclization of 8b and 8c.
The preferential Nꢀcyclization also extends to the cyclization of other olefinic amide
substrates of varying scaffolds. Table 2 shows the scope of the halolactamization reaction,
where a structurally diverse range of products are displayed. These examples include
monocyclic 6ꢀmembered lactam (9a), cyclic carbamates (9d and 9e), lactams with aromatic
scaffolds (9f, 9i and 9k), morpholines (9g and 9h) and piperazine system (9j). Notably,
medium ringꢀsized lactams 9l–9q could also be furnished by using this catalytic protocol. In
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the case of formations of 9l and 9n/9o, attempts were made to synthesize these lactams via
palladium catalysis8a,8b as a comparison and no reaction was observed. In general, the lactams
were achieved with good yields and selectivities.21 We then explored the possibility of further
chemical manipulations on the bromolactam products. Gratifyingly, 9k could undergo an
efficient oneꢀpot denosylation and sulfenylation reaction to give lactam 11 in good yield
(Scheme 4).
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Scheme 4. One-pot Denosylation and Sulfenylation of 9k.
To understand the effect of component variations on the catalysis, we performed
further studies using reconstituted catalyst systems (Scheme 5). Thiourea 10, a sulfur
analogue of 6, gave a lower Nꢀselectivity than urea 6 under the same reaction conditions
(Scheme 4, entry 1). Modifications to urea 6 were also performed. The N,N’ꢀdimethylurea 12
returned with lower Nꢀcyclized product conversion, suggesting that the NꢀH might be
involved in the reaction mechanism, possibly via a dual hydrogen bonding interaction (entry
2).22 Interestingly, when the aniline partner was replaced with triethylamine, a similar ratio of
9a/9a’ was obtained. This may suggest that the aromatic and the NꢀH moieties do not play
crucial roles in controlling the selectivity (entry 3). It is noteworthy that triethylamine alone
could not promote the bromolactamization (Table 1, entry 2), indicating that the three
components might work cooperatively in the reaction (vide infra). A similar selectivity was
also obtained when 2ꢀbromopyridine (13) was used in place of aniline 7 which further
suggests that the NꢀH in this weakly basic aniline component is not a dominant factor (entry
4).
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Table 2. Scope of the Bromolactamization of 8a
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a Reactions were carried out with olefinic amide 6a (0.3 mmol), white solid catalyst (2/6/7, 3:1:1) (0.015 mmol)
b
and NBS (0.45 mmol) in CH2Cl2 (6 mL) at 40 oC in the absence of light. Isolated yield by column
chromatography. c c.a. 25% of Oꢀcyclized product was detected as determined by 1H NMR on the crude reaction
e
mixture. d 2.5 eq NBS was used. The parentheses indicate the yield of the bromolactam when the reaction was
carried out with 8 (0.3 mmol), Pd(OAc)2 catalyst (0.03 mmol), CuBr2 (1.5 mmol) and K2CO3 (0.6 mmol) in
THF (3 mL) at 25 °C in the absence of light for 24 h. f Determined by 1H NMR.
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Scheme 5. Studies on the Effect of Different Components Using Reconstituted Catalyst
Systems.
In the course of the investigation, we realized that while both urea 6 alone and a
mixture of urea 6/NBS were insoluble in CH2Cl2, a DMAP (2)/urea 6/NBS mixture dissolved
1
quickly in CH2Cl2 to give a colourless solution. Preliminary studies by H NMR indicated
that DMAP (2), urea 6 and NBS might interact with one another,15, 23 which could account for
these solubility differences. We had also suspected that the three components might react
irreversibly to give a new catalytic species in situ. Nonetheless, the possibility was unlikely to
1
happen on the basis of the H NMR studies: the chemical shifts and integrations of the
individual components perfectly matched with the signals in the 3:1:1 mixture. To further
verify this suspicion, a set of careful experiments were performed. The threeꢀcomponent
system DMAP (2), urea 6 and aniline 7 were stirred with NBS for 1 hour in CH2Cl2 at 40 °C.
1.2 Equivalent of 1,3,5ꢀtrimethoxybenzene was then added to the mixture to capture the
electrophilic Br. After that, monobrominated 1,3,5ꢀtrimethoxybenzene was obtained
quantitatively and more crucially, all the three components could be recovered. This suggests
that the threeꢀcomponent system might work cooperatively through weak interactions (e.g.
hydrogen bonding), rather than forming a new species irreversibly.
While a definite mechanism awaits thorough investigation, we could summarize the
overall observations on the basis of these studies: (1) aniline 7, DMAP (2), and urea 6, play
unique roles in this catalytic protocol and the three catalytic partners might have a synergetic
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effect; (2) the relatively weaker base aniline 7 and the relatively stronger base DMAP (2)
5
6
seem to serve different functions in this catalytic protocol.
7
8
9
In summary, a facile and selective bromolactamization of olefinic amides has been
developed using an unprecedented threeꢀcomponent catalyst system, with NBS as the
stoichiometric brominating agent. NꢀCyclization preferentially occurs over Oꢀcyclization,
leading to the formation of a structurally diverse range of lactams including both small and
mediumꢀring sizes.
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EXPERIMENTAL SECTION
General Information
All reactions that required anhydrous conditions were carried out via standard procedures
under nitrogen atmosphere. Commercially available reagents were used as received. The
solvents were dried and purified over a solvent purification system. Thinꢀlayer
chromatography (TLC) was performed using precoated silica gel foils. Chromatographic
purification was performed on silica gel (0.040ꢀ0.063 mm). Infrared spectra were recorded on
a FTIR spectrophotometer and reported in wave numbers (cmꢀ1). Melting points were
1
determined on a melting point apparatus. H NMR and 13C NMR spectra were recorded on
either a spectrometer operating at 300 MHz for protons and 75 MHz for carbon nuclei or a
1
spectrometer operating at 500 MHz for protons and 125 MHz for carbon nuclei. Data for H
NMR spectra are reported as follows: chemical shift (δ) in parts per million (multiplicity,
1
coupling constant (Hz), integration). Data for H NMR spectra are referenced to the center
line of CDCl3 (δ 7.26) as the internal standard. Data for 13C NMR spectra are referenced to
the center line of CDCl3 (δ 77.0) as the internal standard. Highꢀresolution mass spectra were
obtained on a mass spectrometer in ESI or EI mode using a TOF mass analyzer.
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Preparation of Three Component Catalyst System 2/6/7 (3:1:1). N,Nꢀ
Dimethylaminopyridine (DMAP) (122 mg, 1.0 mmol, 1.0 eq) was added to a solution of 3,5ꢀ
bis(trifluoromethyl)phenyl isocyanate (173 ꢁL, 1.0 mmol, 1.0 eq) in toluene (2 mL) and
stirred for 0.5 h. Upon completion, the mixture was filtered to obtain the product as a white
solid. The solid was then recrystallized from hot toluene, filtered and dried under vacuum.
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Three-component catalyst system: DMAP (2), 1,3-bis(3,5
bis(trifluoromethyl)phenyl)urea (6) and 3,5-bis(trifluoromethyl)aniline (7) (ca. 3:1:1)
White solid (377.1 mg, quantitative yield); mp 75.6 – 77.3 °C; IR (KBr): 3108, 2939, 1738,
1608, 1385, 1282, 1172, 1123, 995 cmꢀ1; 1H NMR (500 MHz, CDCl3): DMAP (2): δ 8.21 (d,
J = 6.9 Hz, 2H), 6.54 (d, J = 7.0 Hz, 2H), 3.03 (s, 3H); 1,3ꢀBis(3,5ꢀ
bis(trifluoromethyl)phenyl)urea (6):
δ 7.87 (s, 1.3 H), 7.46 (s, 0.7 H); 3,5ꢀ
bis(trifluoromethyl)aniline (7): δ 7.19 (s, 0.3 H), 7.02 (s, 0.7 H); 13C NMR (75 MHz, CDCl3):
DMAP (2): δ 154.6, 148.9, 106.9, 38.9; 1,3ꢀBis(3,5ꢀbis(trifluoromethyl)phenyl)urea (6): δ
152.7, 140.8, 132.0 (q, J = 33.3 Hz), 125.0, 121.4, 118.1; 3,5ꢀbis(trifluoromethyl)aniline (7):
δ 147.7, 132.0 (q, J = 33.3 Hz), 125.2, 113.9, 111.0.
Representative procedure for the preparation of olefinic amides 8a to 8c and 8f to 8n.
The method is based on that in the literature.8b 5ꢀHexenoic acid (119 ꢁL, 1.0 mmol, 1.0 eq)
was added into a solution of 1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide hydrochloride,
EDCI (250 mg, 1.3 mmol, 1.3 eq) and DMAP (171 mg, 1.4 mmol, 1.4 eq) in CH2Cl2 (4 mL)
at 0 °C. pꢀToluenesulfonamide, TsNH2 (205 mg, 1.2 mmol, 1.2 eq) was then added in one
portion to the mixture. The mixture was allowed to warm slowly to room temperature and
stirred for 24 h. Upon completion, the mixture was diluted with CH2Cl2 (6 mL) and washed
with 1 N HCl solution (10 mL). The organic layer was removed and the aqueous layer
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extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were dried with Na2SO4
and concentrated under vacuum. Purification by flash column chromatography
(CH2Cl2:EtOAc 9:1) gave the amide 8a.
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Representative procedure for the preparation of olefinic amides 8d and 8e. The method
is based on that in the literature.24 pꢀToulenesulfonyl isocyanate (458 ꢁL, 3.0 mmol, 1.5 eq)
was added dropwise to a solution of allyl alcohol (136 ꢁL, 2.0 mmol, 1.0 eq) in CH2Cl2 (5
mL) at 0 °C. The mixture was allowed to warm slowly to room temperature and stirred for
0.5 h. Upon completion, the mixture was diluted with water (5 mL). The organic layer was
removed and the aqueous layer extracted with CH2Cl2 (2 x 5 mL). The combined organic
layers were dried with Na2SO4 and concentrated under vacuum. Purification by flash column
chromatography (CH2Cl2:EtOAc 9:1) gave the amide 8d.
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N-tosylhex-5-enamide (8a)25
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Clear oil (211.9 mg, 79% yield); H NMR (500 MHz, CDCl3): δ 9.23 (br, 1H), 7.93 (d, J =
8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 5.70ꢀ5.61 (m, 1H), 4.94ꢀ4.89 (m, 2H), 2.42 (s, 3H),
2.26 (t, J = 7.6 Hz, 2H), 1.97 (q, , J = 7.1 Hz, 2H), 1.64 (q, J = 7.6 Hz, 2H); 13C NMR (125
MHz, CDCl3): δ 171.1, 145.0, 137.2, 135.6, 129.5, 128.2, 115.5, 35.3, 32.6, 23.2, 21.6; MS
(ESI) [M ꢀ H]‾: 266.3.
2-allyl-N-tosylbenzamide (8b)25
White solid (299.7 mg, 95% yield); 1H NMR (500 MHz, CDCl3): δ 9.16 (br, 1H), 8.02 (d, J =
8.3 Hz, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.43ꢀ7.37 (m, 3H), 7.24 (m, 2H), 5.87ꢀ5.79 (m, 1H),
4.94 (dd, J = 10.1, 1.4 Hz, 1H), 4.84 (dd, J = 17.2, 1.6 Hz, 1H), 3.47 (d, J = 6.2 Hz, 2H), 2.49
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 166.4, 145.0, 139.0, 136.7, 135.3, 132.3, 131.7, 130.8,
129.4, 128.4, 127.8, 126.4, 116.3, 37.1, 21.5; MS (ESI) [M ꢀ H]‾: 314.3.
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1-allyl-N-tosyl-1H-indole-2-carboxamide (8c)25
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White solid (339.8 mg, 96% yield); 1H NMR (300 MHz, CDCl3): δ 9.60 (br, 1H), 8.09 (d, J =
8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.34ꢀ7.28 (m, 5H), 7.16ꢀ7.11 (m, 1H), 5.93ꢀ5.82 (m,
1H), 5.06 (d, J = 5.0 Hz, 2H), 5.01 (d, J = 10.4 Hz, 1H), 4.84 (d, J = 17.1 Hz, 1H), 2.42 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 158.8, 145.0, 139.5, 135.7, 133.4, 129.6, 128.3, 127.2,
125.7, 125.7, 122.8, 121.1, 116.3, 110.6, 109.1, 46.8, 21.6; MS (ESI) [M ꢀ H]‾: 353.3.
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allyl tosylcarbamate (8d)24
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Colourless oil (460.3 mg, 90% yield); H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 8.2 Hz,
2H), 7.34 (d, J = 8.2 Hz, 2H), 5.85ꢀ5.77 (m, 1H), 5.29ꢀ5.21 (m, 2H), 4.56 (d, J = 5.7 Hz, 2H),
2.44 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 150.1, 145.1, 135.5, 130.8, 129.6, 128.4, 119.4,
67.3, 21.6; MS (ESI) [M ꢀ H]‾: 254.1.
2-phenylallyl tosylcarbamate (8e)
Colourless oil (575.6 mg, 87% yield); IR (Neat): 3246, 3021, 1751, 1427, 1216, 1160, 1090,
759 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H), 7.37ꢀ7.33 (m, 5H), 7.29 (d,
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J = 8.2 Hz, 2H), 5.55 (s, 1H), 5.33 (s, 1H), 4.99 (s, 2H), 2.45 (s, 3H); C NMR (125 MHz,
CDCl3): δ 150.4, 144.9, 141.3, 137.4, 135.4, 129.5, 128.5, 128.2, 128.1, 125.8, 116.3, 67.9,
21.6; HRMS (ESI) calcd for C17H16NO4S m/z [M ꢀ H]ꢀ: 330.0806; found: 330.0808.
N-tosyl-2-vinylbenzamide (8f)
Clear paste (276.9 mg, 92% yield); IR (Neat): 3555, 1705, 1409, 1346, 1168, 1051, 737 cmꢀ1;
1H NMR (500 MHz, CDCl3): δ 8.94 (br, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 7.6 Hz,
1H), 7.44ꢀ7.39 (m, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.85 (dd, J = 17.7,
11.4 Hz, 1H), 5.60 (d, J = 17.6 Hz, 1H), 5.30 (d, J = 11.4 Hz, 1H), 2.43 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 166.0, 145.1, 137.1, 135.3, 133.7, 131.8, 131.1, 129.5, 128.5, 127.9,
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127.7, 127.0, 118.1, 21.6; HRMS (ESI) calcd for C16H16NO3S m/z [M + H]+: 302.0845; found:
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2-(2-methylallyloxy)-N-tosylacetamide (8g)
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Clear oil (267.4 mg, 94% yield); IR (Neat): 3656, 3348, 1727, 1418, 1598, 1418, 1160, 856
cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 9.01 (br, 1H), 7.96 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 8.2
Hz, 2H), 4.95 (s, 1H), 4.93 (s, 1H), 3.92 (s, 2H), 3.86 (s, 2H), 2.42 (s, 3H), 1.71 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 167.5, 145.2, 140.0, 135.4, 129.5, 128.4, 114.3, 75.6, 68.6, 21.6,
19.2; HRMS (ESI) calcd for C13H17NNaO4S m/z [M + Na]+: 306.0770; found: 306.0777.
2-(2-phenylallyloxy)-N-tosylacetamide (8h)
Yellow oil (282.4 mg, 82% yield); IR (Neat): 3344, 3260, 3024, 2920, 1726, 1417, 1350,
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1158, 1087 cmꢀ1; H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2,
1.3 Hz, 2H), 7.39ꢀ7.34 (m, 3H), 7.30 (d, J = 8.2 Hz, 2H), 5.58 (s, 1H), 5.30 (s, 1H), 4.45 (s,
2H), 3.92 (s, 2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4, 145.1, 142.5, 137.4,
135.3, 129.4, 129.6, 128.3, 128.2, 125.9, 116.4, 73.6, 68.4, 21.5; HRMS (ESI) calcd for
C18H19NNaO4S m/z [M + Na]+: 368.0927; found: 368.0936.
2-(2-methylallyl)-N-tosylbenzamide (8i)
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Clear paste (287.4 mg, 87% yield); IR (Neat): 3257, 3021, 1706, 1411, 1216, 1167 cmꢀ1; H
NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 7.6, 1.3 Hz, 1H), 7.41 (dt, J
= 7.6, 1.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.27 (dt, J = 7.6, 1.3 Hz, 1H), 7.20 (t, J = 7.6 Hz,
1H), 4.77 (s, 1H), 4.27 (s, 1H), 3.38 (s, 2H), 2.45 (s, 3H), 1.69 (s, 3H); 13C NMR (125 MHz,
CDCl3): 166.1, 146.2, 145.1, 137.8, 135.5, 133.2, 131.7, 130.8, 129.5, 128.6, 128.4, 126.9,
112.7, 41.2, 22.9, 21.7; HRMS (ESI) calcd for HRMS (ESI) calcd for C18H18NO3S m/z [M ꢀ
H]ꢀ: 328.1013; found: 328.1011.
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1-allyl-5-chloro-N-tosyl-1H-indole-2-carboxamide (8j)
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Yellow solid (350.5 mg, 90% yield); mp 185.9ꢀ186.9 °C; IR (KBr): 3361, 3264, 1704, 1517,
1457, 1163, 1080, 915 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 9.32 (br, 1H), 8.03 (d, J = 8.2 Hz,
2H), 7.58 (d, J = 1.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.26ꢀ7.24 (m, 2H), 7.13 (s, 1H), 5.89ꢀ
5.82 (m, 1H), 5.05ꢀ5.01 (m, 3H), 4.82 (d, J = 17.1 Hz, 1H), 2.44 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 158.5, 145.2, 137.8, 135.6, 133.2, 129.8,129.7, 128.5, 126.9, 126.5, 126.4, 121.9,
116.7, 112.0, 108.0, 47.1, 21.7; HRMS (ESI) calcd for C19H18 35ClN2O3S m/z [M + H]+:
389.0721; found: 389.0731.
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2-allyl-N-(4-nitrophenylsulfonyl)benzamide (8k)
Pale yellow solid (329.0 mg, 95% yield); mp 180.7ꢀ182.7 °C; IR (KBr): 3166, 3109, 1686,
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1527, 1431, 1356, 1312, 1249, 1064, 845 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.59 (br, 1H),
8.43 (d, J = 8.3 Hz, 2H), 8.36 (d, J = 8.7 Hz, 2H), 7.49ꢀ7.46 (m, 2H), 7.33ꢀ7.27 (m, 2H),
5.93ꢀ5.85 (m, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.81 (d, J = 17.3 Hz, 1H), 3.49 (d, J = 5.8 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ 165.9, 150.9, 143.9, 139.1, 137.0, 132.5, 131.8, 131.6,
130.2, 128.0, 126.9, 124.1, 116.8, 37.3; HRMS (ESI) calcd for C16H14N2NaO5S m/z [M +
Na]+: 369.0516; found: 369.0517.
2-(but-3-enyl)-N-(4-nitrophenylsulfonyl)benzamide (8l)
White solid (306.9 mg, 85% yield); mp 124.2ꢀ126.8 °C; IR (KBr): 3113, 2866, 1683, 1531,
1179, 1067, 847 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J = 8.9 Hz, 2H), 8.32 (d, J =
8.9 Hz, 2H),7.43ꢀ7.38 (m, 2H), 7.25ꢀ7.22 (m, 2H), 5.63ꢀ5.55 (m, 1H), 4.87ꢀ4.81 (m, 2H),
2.72 (t, J = 7.8 Hz, 2H), 2.12 (q, J = 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 166.4,
150.8, 143.8, 141.8, 137.1, 132.2, 131.5, 131.2, 130.0, 127.3, 126.3, 124.1, 115.5, 35.3, 32.4;
HRMS (ESI) calcd for C17H15N2O5S m/z [M ꢀ H]‾: 359.0707; found: 359.0722.
1-(but-3-enyl)-N-(4-nitrophenylsulfonyl)-1H-indole-2-carboxamide (8m)
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Yellow solid (367.1 mg, 92% yield); mp 166.4ꢀ168.4 °C; IR (KBr): 3289, 1694, 1535, 1421,
1157, 1060, 894 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.40ꢀ8.34 (m, 4H), 7.64 (d, J = 8.2 Hz,
1H), 7.38ꢀ7.35 (m, 2H), 7.18ꢀ7.15 (m, 2H), 5.69ꢀ5.61 (m, 1H), 4.92ꢀ4.88 (m, 2H), 4.48 (t, J =
6.9 Hz, 2H), 2.43 (q, J = 6.9 Hz, 2H), 13C NMR (125 MHz, CDCl3): δ 158.5, 150.8, 144.1,
139.6, 134.3, 130.0, 126.6, 126.3, 125.5, 124.2, 122.8, 121.5, 117.4, 110.7, 109.0, 44.2, 34.6;
HRMS (ESI) calcd for C19H16N3O5S m/z [M ꢀ H]‾: 398.0816; found: 398.0833.
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2-(but-3-enyloxy)-N-(4-nitrophenylsulfonyl)acetamide (8n)
Pale yellow solid (251.0 mg, 80% yield); mp 94.6ꢀ96.2 °C; IR (KBr): 3304, 3285, 3073, 1743,
1532, 1409, 1353, 1188, 939 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 9.05 (br, 1H), 8.40 (d, J =
8.9 Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H), 5.84ꢀ5.76 (m, 1H), 5.18ꢀ5.14 (m, 2H), 3.95 (s, 2H),
3.59 (t, J = 6,3 Hz, 2H), 2.38 (q, J = 6,3 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 167.7, 150.9,
143.7, 134.1, 129.9, 124.1, 117.9, 71.3, 69.6, 33.6; HRMS (ESI) calcd for C12H13N2O6S m/z
[M ꢀ H]ꢀ: 313.0500; found: 313.0503.
2-methylallyl 2-(4-nitrophenylsulfonylcarbamoyl)cyclohexanecarboxylate (8o)
Pale yellow solid (365.3 mg, 89% yield); mp 116.4ꢀ118.2 °C; IR (KBr): 3177, 2953, 2872,
1704, 1529, 1442, 1353, 1308, 1194, 1086 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.93 (br, 1H),
8.34 (d, J = 8.8 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H), 4.92ꢀ4.78 (m, 2H), 4.41ꢀ4.30 (m, 2H),
2.92ꢀ2.80 (m, 1H), 2.71ꢀ2.64 (m, 1H), 2.14ꢀ2.04 (m, 1H), 1.99ꢀ1.88 (m, 1H), 1.85ꢀ1.70 (m,
2H), 1.66 (s, 3H), 1.62ꢀ1.55 (m, 1H), 1.50ꢀ1.30 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
173.5, 172.1, 150.6, 144.0, 139.4, 129.9, 123.9, 112.9, 68.0, 43.9, 43.1, 26.3, 26.0, 23.6, 23.0,
19.3; HRMS (ESI) calcd for C18H21N2O7S m/z [M ꢀ H]‾: 409.1075; found: 409.1064.
Representative Procedure for the Bromolactamization of Tosylated Amides. To a
solution of amide 8a (80.2 mg, 0.3 mmol, 1.0 eq) in CH2Cl2 (6 mL) in the dark at 40°C was
added white solid catalyst (consisting of DMAP (2) (1.83 mg, 0.015 mmol, 0.05 eq), urea 6
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(2.42 mg, 0.005 mmol, 0.017 eq) and aniline 7 (1.15 mg, 0.005 mmol, 0.017 eq), and Nꢀ
bromosuccinimide (80.1 mg, 0.45 mmol, 1.5 eq)). The mixture was stirred for 0.5 h at 40°C
and quenched by saturated Na2SO3 (6 mL). The solution was diluted with water (4 mL) and
extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were washed with brine
(20 mL), dried with Na2SO4, filtered and concentrated under vacuum. The residue was
purified by flash column chromatography (Hexane : EtOAc 9:1 as eluent) to yield the
corresponding lactam 9a.
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6-(bromomethyl)-1-tosylpiperidin-2-one (9a)
Pale yellow solid (63.6 mg, 61% yield); mp 130.6ꢀ131.9 °C; IR (KBr): 2954, 1696, 1348,
1160, 1088, 803 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.30 (d, J =
8.2 Hz, 2H), 4.81ꢀ4.78 (m, 1H), 3.80 (dd, J = 10.1, 3.2 Hz, 1H), 3.52 (t, J = 10.1 Hz, 1H),
2.51ꢀ2.32 (m, 3H), 2.44 (s, 3H), 1.88ꢀ1.86 (m, 2H), 1.77ꢀ1.74 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 169.8, 145.0, 136.0, 129.3, 128.9, 56.5, 33.3, 32.6, 25.1, 21.6, 15.8; HRMS (ESI)
calcd for C13H1779BrNO3S m/z [M + H]+: 346.0107; found: 346.0102.
3-(bromomethyl)-2-tosyl-3,4-dihydroisoquinolin-1(2H)-one (9b)
Pale yellow solid (99.4 mg, 84% yield); mp 141.3ꢀ142.6 °C; IR (KBr): 3070, 2960, 1692,
1600, 1338, 1245, 737 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 8.5 Hz, 2H), 7.94 (d,
J = 7.8 Hz, 1H), 7.51 (t, J = 6.7 Hz, 1H), 7.34ꢀ7.32 (m, 3H), 7.25 (d, J = 7.8 Hz, 1H), 5.17ꢀ
5.13 (m, 1H), 3.63 (dd, J = 10.1, 3.9 Hz, 1H), 3.49 (d, J = 16.7 Hz, 1H), 3.33 (dd, J = 16.5,
5.5 Hz, 1H), 3.23 (t, J = 10.3 Hz, 1H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 162.0,
145.1, 135.9, 135.4, 134.0, 129.4, 128.9, 128.8, 128.5, 127.7, 127.4, 55.4, 30.9, 30.1, 21.6;
HRMS (ESI) calcd for C17H1779BrNO3S m/z [M + H]+: 394.0107; found: 394.0108.
10-bromo-3-(bromomethyl)-2-tosyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (9c)
Pale yellow solid (141.3 mg, 92% yield); mp 118.0ꢀ120.0 °C; IR (KBr): 3058, 2924, 1689,
1
1523, 1348, 1166, 1060, 744 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 8.2 Hz, 2H),
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7.67ꢀ7.64 (m, 1H), 7.49ꢀ7.45 (m, 1H), 7.37ꢀ7.34 (m, 3H), 7.28ꢀ7.24 (m, 1H), 5.28 (dd, J = 6.3,
4.4 Hz, 1H), 5.04 (dd, J = 13.3, 4.4 Hz, 1H), 4.23 (d, J = 13.3 Hz, 1H), 3.67 (d, J = 13.3 Hz,
1H), 3.66 (d, J = 10.8 Hz, 1H), 3.27 (dt, J = 11.4, 3.2 Hz, 1H), 2.44 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 155.3, 145.6, 135.9, 135.5, 129.7, 129.1, 127.7, 127.6, 122.2, 121.6, 121.6,
110.0, 100.4, 56.0, 41.9, 29.4, 21.7; HRMS (ESI) calcd for C19H17 79Br2N2O3S m/z [M + H]+:
510.9321; found: 510.9323.
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4-(bromomethyl)-3-tosyloxazolidin-2-one (9d)8a
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Pale yellow solid (52.4 mg, 52% yield); H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 8.9 Hz,
2H), 7.37 (d, J = 7.6 Hz, 2H), 4.74ꢀ4.69 (m, 1H), 4.44 (t, J = 8.8 Hz, 1H), 4.43 (dd, J = 9.5,
3.8 Hz, 1H), 3.77 (dd, J = 10.7, 2.5 Hz, 1H), 3.71 (dd, J = 10.7, 6.9 Hz, 1H), 2.45 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 151.7, 146.0, 134.3, 129.9, 128.5, 66.9, 56.1, 33.1, 21.7; MS
(ESI) [M + Na]+: 354.0.
4-(bromomethyl)-4-phenyl-3-tosyloxazolidin-2-one (9e)
White solid (66.4 mg, 54% yield); mp 158.0ꢀ159.4 °C; IR (KBr): 3036, 1621, 1319, 1163,
1077, 966 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.44ꢀ7.41 (m, 3H),
7.31ꢀ7.28 (m, 4H), 5.03 (d, J = 8.2 Hz, 1H), 4.76 (d, J = 8.2 Hz, 1H), 3.75 (d, J = 12.0 Hz,
1H), 3.71 (d, J = 12.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 158.5, 143.4,
138.2, 136.5, 129.8, 129.3, 129.2, 127.3, 124.3, 88.2, 75.7, 37.3, 21.5; HRMS (ESI) calcd for
C17H1779BrNO4S m/z [M + H]+: 410.0056; found: 410.0045.
3-(bromomethyl)-2-tosylisoindolin-1-one (9f)
White solid (72.1 mg, 63% yield); mp 204.5ꢀ205.2 °C; IR (KBr): 3062, 1726, 1596, 1360,
1172, 1097, 814 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.2 Hz, 2H), 7.80 (d, J =
7.6 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.55ꢀ7.50 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.53 (d, J =
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2.5 Hz, 1H), 4.28 (dd, J = 11.4, 5.1 Hz, 1H), 4.03 (dd, J = 11.4, 2.5 Hz, 1H), 2.42 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 166.1, 145.4, 143.3, 135.4, 134.2, 130.0, 129.6, 129.6, 128.5,
124.9, 122.5, 60.8, 34.0, 21.7; HRMS (ESI) calcd for C16H15 79BrNO3S m/z [M + H]+:
379.9951; found: 379.9949.
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5-(bromomethyl)-5-methyl-4-tosylmorpholin-3-one (9g)
White solid (67.8 mg, 62% yield); 125.5ꢀ127.4 °C; IR (KBr): 2978, 1714, 1596, 1464, 1340,
979 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H),
4.21ꢀ4.07 (m, 5H), 3.48 (d, J = 12.7 Hz, 1H), 2.43 (s, 3H), 1.84 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 167.8, 145.3, 136.6, 129.4, 129.2, 73.0, 69.5, 64.6, 35.2, 21.7, 21.3; HRMS (ESI)
calcd for C13H1779BrNO4S m/z [M + H]+: 362.0056; found: 362.0043.
5-(bromomethyl)-5-phenyl-4-tosylmorpholin-3-one (9h)
Yellow solid (72.7 mg, 57% yield); mp 174.0ꢀ176.0 °C; IR (KBr): 2931, 1725, 1696, 1280,
1175, 1136 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.56 (d, J = 8.2 Hz, 2H), 7.50ꢀ7.48 (m, 2H),
7.41ꢀ7.40 (m, 3H), 7.19 (d, J = 8.2 Hz, 2H), 4.71ꢀ4.63 (m, 2H), 4,43 (d, J = 12.6 Hz, 1H),
4.38 (d, J = 17.7 Hz, 1H), 4.30 (d, J = 17.1 Hz, 1H), 3.85 (d, J = 12.6 Hz, 1H), 2.40 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 167.9, 145.3, 137.0, 135.6, 130.1, 128.7, 128.6, 128.5, 127.1,
75.3, 69.7, 67.9, 34.9, 21.6; HRMS (ESI) calcd for C18H1879BrNNaO4S m/z [M + Na]+:
446.0032; found: 446.0037.
3-(bromomethyl)-3-methyl-2-tosyl-3,4-dihydroisoquinolin-1(2H)-one (9i)
Pale yellow solid (72.6 mg, 59% yield); mp 124.4ꢀ126.4 °C; IR (KBr): 2915, 1691, 1605,
1348, 1295, 1170, 809 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 8.2 Hz, 2H), 7.81 (d,
J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.34ꢀ7.31 (m, 3H), 7.21 (d, J = 7.6 Hz, 2H), 4.06 (d,
J = 10.1 Hz, 1H), 3.94 (d, J = 10.1 Hz, 1H), 3.55 (d, J = 15.8 Hz, 1H), 3.02 (d, J = 15.8 Hz,
1H), 2.43 (s, 3H), 2.01 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.7, 144.4, 138.0, 150.0,
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133.8, 129.2, 128.6, 128.5, 128.2, 127.7, 127.3, 65.2, 40.7, 37.8, 25.6, 21.6; HRMS (ESI)
calcd for C18H1979BrNO3S m/z [M + H]+: 408.0264; found: 408.0271.
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10-bromo-3-(bromomethyl)-8-chloro-2-tosyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one
(9j)
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Yellow solid (150.9 mg, 92% yield); mp 254.6ꢀ255.9 °C; IR (KBr): 1681, 1522, 1352, 1252,
1167, 1079 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.04 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 1.9 Hz,
2H), 7.42ꢀ7.40 (m, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 5.29ꢀ5.26 (m, 1H),
5.01 (dd, J = 13.3, 1.3 Hz, 1H), 4.24 (dd, J = 13.3, 3.2 Hz, 1H), 3.69ꢀ3.66 (m, 1H), 3.25 (t, J
= 10.7 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 155.1, 145.8, 135.4, 134.3,
129.8, 129.1, 128.5, 128.4, 128.3, 122.8, 121.0, 111.3, 99.4, 55.9, 42.1, 29.3, 21.7; HRMS
(ESI) calcd for C19H16 79Br2 35ClN2O3S m/z [M + H]+: 544.8931; found: 544.8918.
3-(bromomethyl)-2-(4-nitrophenylsulfonyl)-3,4-dihydroisoquinolin-1(2H)-one (9k)
Pale yellow solid (92.1 mg, 72% yield); mp 165.2ꢀ167.2 °C; IR (KBr): 3429, 1700, 1605,
1
1532, 1354, 1173, 1053, 855 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.38 (d, J = 8.7 Hz, 2H),
8.33 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.7 Hz,
1H), 7.29 (d, J = 7.7 Hz, 1H), 5.18ꢀ5.15 (m, 1H), 3.62ꢀ3.59 (m, 1H), 3.54 (d, J = 20.5 Hz,
1H), 3.40 (dd, J = 16.7, 5.5 Hz, 1H), 3.30ꢀ3.26 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 162.3,
150.7, 144.5, 135.5, 134.7, 130.5, 129.0, 128.7, 128.1, 126.9, 124.0, 55.8, 30.7, 30.5; HRMS
(ESI) calcd for C16H1379BrN2NaO5S m/z [M + Na]+: 446.9621; found: 446.9612.
3-(bromomethyl)-2-(4-nitrophenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one
(9l)
White solid (65.7 mg, 50% yield); mp 181.8ꢀ183.9 °C; IR (KBr): 2945, 1704, 1588, 1528,
1339, 1160, 748 cmꢀ1; 1H NMR: (CDCl3, 500 MHz): δ 8.36 (d, J = 8.2 Hz, 2H), 8.25 (d, J =
8.2 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.25
(m, 1H), 4.41ꢀ4.35 (m, 1H), 3.64ꢀ3.60 (m, 1H), 3.57ꢀ3.54 (m, 1H), 2.99ꢀ2.92 (m, 1H), 2.85ꢀ
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2.81 (m, 1H), 2.35ꢀ2.20 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 170.2, 150.0, 147.4, 139.1,
134.1, 131.2, 129.6, 129.2, 128.6, 127.9, 124.0, 81.3, 33.3, 31.6, 29.1; HRMS (ESI) calcd for
C17H1679BrN2O5S m/z [M + H]+: 438.9958; found: 438.9955.
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11-bromo-3-(bromomethyl)-2-(4-nitrophenylsulfonyl)-2,3,4,5-tetrahydro-1H-
[1,4]diazepino[1,2-a]indol-1-one (9m)
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Orange solid (67.5 mg, 40% yield); mp 199.5ꢀ200.7 °C; IR (KBr): 3105, 1687, 1531, 1355,
1
1178, 1082 cmꢀ1; H NMR: (CDCl3, 500 MHz): δ 8.47 (d, J = 9.5 Hz, 2H), 8.43 (d, J = 8.9
Hz, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.49ꢀ7.46 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.29ꢀ7.28 (m,
1H), 4.94 (m, 1H), 4.69ꢀ4.65 (m, 1H), 4.58ꢀ4.52 (m 1H), 3.10 (m, 1H), 2.70ꢀ2.57 (m, 2H),
13
2.28ꢀ2.26 (m, 1H); C NMR (125 MHz, CDCl3): δ 150.7, 144.1, 135.8, 130.9, 127.7, 126.9,
126.2, 124.3, 123.8, 122.1, 121.9, 109.8, 101.1, 40.8, 38.0, 33.1, 32.7; HRMS (ESI) calcd for
C19H16 79Br2N3O5S m/z [M + H]+: 555.9172; found: 555.9160.
5-(bromomethyl)-4-(4-nitrophenylsulfonyl)-1,4-oxazepan-3-one (9n) and 6-bromo-4-(4-
nitrophenylsulfonyl)-1,4-oxazocan-3-one (9o) as a mixture (ca. 1:0.35)
Offꢀwhite solid (68.4 mg, 58% yield); mp 178.5ꢀ180.0 °C; IR (KBr): 1702, 1531, 1352, 1167,
1
855 cmꢀ1; H NMR: (CDCl3, 500 MHz): 9n: δ 8.37 (d, J = 8.9 Hz, 2H), 8.21 (d, J = 8.9 Hz,
2H), 4.79ꢀ4.75 (m, 1H), 4.47ꢀ4.35 (m, 2H), 4.14ꢀ4.09 (m, 1H), 4.00ꢀ3.90 (m, 2H), 7.76 (dd, J
= 12.0, 6.9 Hz, 1H), 2.73ꢀ2.68 (m, 1H), 2.27ꢀ2.20 (m, 1H); 9o: δ 8.37 (d, J = 8.9 Hz, 2H),
8.21 (d, J = 8.8 Hz, 2H), 4.95 (dd, J = 14.5, 10.7 Hz, 1H), 4.63ꢀ4.49 (m, 2H), 4.14ꢀ4.09 (m,
1H), 4.00ꢀ3.90 (m, 2H), 3.73ꢀ3.70 (m, 1H), 2.45ꢀ2.38 (m, 1H), 2.00ꢀ1.97 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 173.4, 172.1, 150.7 (2C), 144.3, 144.0, 130.3, 130.2, 124.0 (2C), 71.6,
70.5, 69.1, 64.9, 56.3, 49.9, 46.8, 46.2, 31.0, 28.5; HRMS (ESI) calcd for C12H1379Br
N2NaO6S m/z [M + Na]+: 414.9570; found: 414.9558.
4-(bromomethyl)-4-methyl-5-(4-nitrophenylsulfonyl)octahydro-1H-
benzo[f][1,4]oxazocine-1,6(3H)-dione
(9p)
and
4-bromo-4-methyl-6-(4-
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nitrophenylsulfonyl)decahydrobenzo[g][1,5]oxazonine-1,7-dione (9q) as a mixture (ca.
1:0.95)
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9
Pale yellow solid (95.8 mg, 65% yield); mp 172.2ꢀ176.1 °C; IR (KBr): 3480, 3118, 2937,
2860, 1751, 1609, 1528, 1448, 1370, 1311, 1260, 1223, 1190, 1086, 1029, 825, 742 cmꢀ1; 1H
NMR: (CDCl3, 500 MHz): 9p: δ 8.40ꢀ8.30 (m, 2H), 8.25ꢀ8.20 (m, 2H), 4.24 (d, J = 7.6 Hz,
1H), 3.99 (d, J = 7.6 Hz, 1H), 3.89ꢀ3.79 (m, 1H), 3.48ꢀ3.40 (m, 1H), 2.94ꢀ2.92 (m, 1H), 2.42ꢀ
2.29 (m, 1H), 2.09ꢀ2.03 (m, 1H), 1.80ꢀ1.75 (m, 2H), 1.57 (s, 3H), 1.51ꢀ1.45 (m, 1H), 1.38ꢀ
1.31 (m, 1H), 1.05ꢀ0.95 (m, 1H), 0.89ꢀ0.82 (m, 1H), 0.61 (t, J = 13.2 Hz, 1H); 9q: δ 8.40ꢀ
8.30 (m, 2H), 8.25ꢀ8.20 (m, 2H), 4.55ꢀ4.51 (m, 1H), 4.41ꢀ4.38 (m, 1H), 3.74ꢀ3.67 (m, 1H),
3.48ꢀ3.40 (m, 1H), 2.87ꢀ2.86 (m, 1H), 2.42ꢀ2.29 (m, 1H), 2.09ꢀ2.03 (m, 1H), 1.73ꢀ1.69 (m,
2H), 1.58 (s, 3H), 1.51ꢀ1.45 (m, 1H), 1.38ꢀ1.31 (m, 1H), 1.05ꢀ0.95 (m, 1H), 0.89ꢀ0.82 (m,
1H), 0.73 (t, J = 13.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 173.3, 173.3, 173.2, 173.1,
150.5 (2C), 144.6, 144.5, 129.5, 129.4, 124.0, 124.0, 84.5, 83.6, 74.1, 72.4, 46.8, 46.4, 41.0,
40.6, 37.5, 35.9, 25.2, 24.4, 24.0, 22.7, 22.6, 22.0, 21.7, 21.4, 21.3, 19.7; HRMS (ESI) calcd
for C18H2179BrN2NaO7S m/z [M + Na]+: 511.0145; found: 511.0134.
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Procedure for the One-pot Denosylation and Sulfenylation of 9k.26 Compound 9k (42.5
mg, 0.1 mmol) was dissolved in MeCN (1.0 mL) and this solution was added to a suspension
of K2CO3 (55.3 mg, 0.4 mmol, 4.0 eq) and PhSH (30.7 ꢁL, 0.3 mmol, 3.0 eq) in MeCN (1.9
mL) at room temperature under nitrogen atmosphere. DMSO (0.1 mL) was then added and
the reaction mixture was stirred for 1 h. After consumption of the starting material was
determined, the reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 4.0
mL). The combined organic extracts were washed with brine (10 mL), dried with Na2SO4,
filtered and concentrated under vacuum. The residue was purified by flash column
chromatography (Hexane : EtOAc 4:1, followed by CH2Cl2 : EtOAc 9:1 as eluent) to yield 11.
3-(phenylthiomethyl)-3,4-dihydroisoquinolin-1(2H)-one (11)
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Pale yellow solid (23.9 mg, 89% yield); mp 134.8ꢀ136.6 °C; IR (KBr): 3439, 3171, 3038,
1
2929, 1658, 1480, 1398, 1330, 1023, 738 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.09 (d, J =
7
8
9
7.6 Hz, 1H), 7.48ꢀ7.45 (m, 1H), 7.43ꢀ7.42 (m, 2H), 7.39ꢀ7.36 (m, 1H), 7.32 (t, J = 7.6 Hz,
2H), 7.29ꢀ7.25 (m, 1H), 7.19ꢀ7.17 (m, 1H), 6.52 (br, 1H), 3.78ꢀ3.73 (m, 1H), 3.23 (dd, J =
13.9, 5.1 Hz, 1H), 3.06 (dd, J = 15.8, 4.4 Hz, 1H), 3.01ꢀ2.96 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 165.7, 137.0, 133.9, 132.4, 131.0, 129.3, 128.5, 128.1, 127.6, 127.3, 127.3, 49.5,
39.5, 33.6; HRMS (ESI) calcd for C16H15NNaOS m/z [M + Na]+: 292.0767; found: 292.0775.
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Acknowledgements
We thank the financial support from The Chinese University of Hong Kong Startup
Funding and National University of Singapore (grant no. 143ꢀ000ꢀ605ꢀ112). We are also
grateful for scholarships to Y. A. Cheng (NGS Scholarship) and W. Z. Yu (NUS Research
Scholarship).
Supporting Information
The Supporting Information is available free of charge on the ACS Publications Website
Xꢀray data of 9b and 9c (CIF file).
1H and 13C NMR spectra of compounds 8aꢀ8o, 9aꢀ9q, 11.
References
(1) (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron
2004, 60, 5273. (b) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33, 354. (c)
Tan, C. K.; Yeung, Y.ꢀY. Chem. Commun. 2013, 49, 7985. (d) Snyder, S. A.; Treitler, D. S.;
Brucks, A. P. Aldrichimica Acta 2011, 44, 27.
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(2) (a) Chemler, S. R.; Bovino, M. T. ACS Catal. 2013, 3, 1076. (b) Zhou, L.; Chen, J.;
Tan, C. K.; Yeung, Y.ꢀY. J. Am. Chem. Soc. 2011, 133, 9164. (c) Xie, W.; Jiang, G.; Liu, H.;
Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.; Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12924.
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Table S1.
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(21) In most cases, the Oꢀcyclized products decomposed upon quenching of the reaction.
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(22) For a dual hydrogen bonding model between thiourea and Nꢀchlorosuccinimide, see:
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