Lewis Basic Sulfide Catalyzed Electrophilic Bromocyclization of Cyclopropylmethyl Amide

Article abstract of DOI:10.1021/acs.orglett.5b02557

A Lewis basic sulfide catalyzed electrophilic bromocyclization of cyclopropylmethyl amide has been developed. The catalytic protocol is applicable to both 1,1- and 1,2-substituted cyclopropylmethyl amides, giving oxazolines and oxazines in good yields and excellent diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.5b02557

Letter
pubs.acs.org/OrgLett
Lewis Basic Sulfide Catalyzed Electrophilic Bromocyclization of
Cyclopropylmethyl Amide
Ying-Chieh Wong,‡,§ Zhihai Ke,†,§ and Ying-Yeung Yeung*,†,‡
†Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, 999077, Hong Kong China
‡Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: A Lewis basic sulfide catalyzed electrophilic bromocyclization of cyclopropylmethyl amide has been developed.
The catalytic protocol is applicable to both 1,1- and 1,2-substituted cyclopropylmethyl amides, giving oxazolines and oxazines in
good yields and excellent diastereoselectivity.
ewis basic chalcogens including selenides and sulfides are
Luseful catalysts to activate halogens in electrophilic
halogenation of olefins. This type of catalytic protocol has
been applied in a number of electrophilic halogenation
reactions such as bromolactonization.1 It is believed that the
π-electrons of the olefin 1 can interact with the electrophilic
halogen of the Lewis basic chalcogen−halogen reactive species
to give the haliranium intermediate A, which is then attacked by
a nucleophile to give the corresponding 1,2-co-halogenated
products 2 (Scheme 1).2
oxazilidines 4 and oxazines 6 catalyzed by triphenylphosphine
sulfide (Scheme 2).
Scheme 2. Lewis Basic Sulfide Catalyzed Electrophilic
Bromocyclization of Cyclopropylmethyl Amide
Scheme 1. Electrophilic Cohalogenation of Olefin Catalyzed
by Lewis Basic Chalcogen
It is noteworthy that oxazoline and oxazine are fundamental
units of many bioactive and pharmaceutically important
compounds.7 In addition, ring opening of oxazines can furnish
1,3-amino alcohols, which are valuable building blocks in many
research areas such as catalysis, materials, and natural products.8
Significant endeavors have been devoted to the synthesis of
substituted oxazolines and oxazines.9
At the outset of our investigation, amide 3a and N-
bromosuccinimide (NBS) were used as the substrate and
brominating agent, respectively (Table 1). The cyclization was
found to be sluggish when no catalyst was applied (Table 1,
entry 1). When 10 mol % of triphenylphosphine sulfide was
used as the Lewis basic sulfide catalyst, the reaction efficiency
was enhanced dramatically and the cyclized product 4a was
obtained in 18% yield after 1 day (Table 1, entry 2). Other
Lewis bases including N,N,N′,N′-tetramethylthiourea, DABCO,
and DMAP were ineffective in catalyzing the reaction (Table 1,
entries 3−5). On the other hand, a survey on various
It is well-known that cyclopropane has high ring strain, which
leads to an ineffective orbital overlapping. As a result, the
hybridized orbitals in the bended bonds (also known as
“banana-bond”) exhibit significant p-character,3 and the
reactivity of cyclopropanes resemble olefins in many cases
such as 2 + 2 type cycloaddition and enolate-type reactions,
implying that cyclopropane can be a suitable candidate for
halogenation reaction in analogue to that of olefin.4 Indeed,
pioneer work by Tikhanushkina and co-workers described an
interesting KICl2 mediated cyclopropane ring-opening reaction
to yield 1,3-dihalide compounds.5,6 We envisioned that
cyclopropane can be used in place of olefin in the
bromocyclization process. Herein, we are pleased to report an
efficient and highly chemo- and diastereoselective bromocyc-
lization of cyclopropylmethyl amides 3 and 5 to give substituted
Received: July 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Conditions Optimization
Scheme 3. Scope of the Bromocyclization of 1,1-Substituted
Cyclopropylmethyl Amides 3
a
b
entry
Br source
catalyst
Ph3PS
solvent
time (h) yield (%)
1
NBS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
168
24
24
24
24
24
24
168
24
24
24
24
24
24
24
24
24
48
16
18
2
NBS
3
NBS
(Me2N)2CS
DABCO
DMAP
NR
NR
NR
15
4
NBS
5
NBS
6
NBP
TABCO
DBH
DBH
DBH
DBH
DBH
DBH
DBH
DBH
DBH
DBH
DBH
Ph3PS
7
Ph3PS
NR
NR
55
8
9
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
Ph3PS
10
11
12
13
14
15
58
(CH2Cl)2
CH3CN
THF
75
21
trace
65
EtOAc
DMF
62
c
16
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
85
c,d
17
82
e
18
79
a
Reactions were carried out with 3a (0.2 mmol), Br source (0.4
mmol), and catalyst (0.02 mmol) in solvent (4 mL) at 25 °C in the
b
c
absence of light. The yields were isolated yields. 4 Å molecular sieves
d
e
were used. 4.0 mmol of 3a was used. 1.0 equiv of DBH was used.
brominating agents was conducted and 1,3-dibromo-5,5-
dimethylhydantoin (DBH) could offer the product with 55%
yield (Table 1, entries 6−9). Again, triphenylphosphine sulfide
remains playing a crucial role in activating the Br source (Table
1, entry 8 vs 9).
Next, a series of solvents were screened. Chlorinated
solvents, in particular, 1,2-dichloroethane, were found to be
more suitable, while other polar solvents such as acetonitrile,
THF, DMF, and ethyl acetate were less effective in driving the
cyclization (Table 1, entries 9−15). Finally, it was realized that
the addition of 4 Å molecular sieves could further improve the
yield to 85% (Table 1, entry 16). The reaction could be
conducted using 1 g of 3a with similar conversion, indicating
that the reaction is readily scalable (Table 1, entry 17).
Although 1 equiv of DBH was found to be sufficient for the
high conversion, a relatively longer reaction time was required
as compared to that of 2 equiv of DBH (Table 1, entry 16 vs
18). With the optimized conditions in hand, a number of
substrates 3 were examined. The scope was found to be quite
broad in which various R1 and R2 substitutions could be
tolerated under this catalytic protocol (Scheme 3). For the R1
substitution, both electron-donating and electron-withdrawing
aryl groups worked well to give the desired oxazolidines 4. In
particular, the 4-tert-butylphenyl substrate 3b gave oxazolidine
4b in 97% yield. When a cyclohexyl substitution was employed,
the alkyl-substituted product 4j was obtained in 80% yield. The
R2 substitution at the cyclopropane could also be varied. As
indicated by examples with substrates 3k−o, a range of
substituents including chloro, bromo, fluoro, and methyl groups
returned the corresponding oxazilines in good yields.
Structurally complicated systems such as 4p (R1 = 2- naphthyl;
R2 = 4-methylphenyl) and 4q (R1 = 3-methoxyphenyl; R2 = 4-
methylphenyl) could be prepared using the same catalytic
a
Reactions were carried out with 3 (0.2 mmol), DBH (0.4 mmol), 4 Å
MS (250 mg), and Ph3PS (0.02 mmol) in (CH2Cl)2 (4 mL) at 25 °C
in the absence of light. Reaction time was 48 h. Reaction time was 12
h. Only dibrominated product was isolated.
b
c
d
protocol. When 4-methoxyphenyl group was used as the R2
substitution, aromatic bromination took place simultaneously
to give dibrominated products (i.e., 4r,s).
Moreover, 1,2-cyclopropylmethyl amides 5 were found to
work equally as well as 1,1-cyclopropylmethyl amides 3. Some
examples are shown in Scheme 4. It is noteworthy that
B
DOI: 10.1021/acs.orglett.5b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Scope of the Bromocyclization of 1,2-Substituted
Cyclopropylmethyl Amides 5
Scheme 6. Transformations of Oxazoline 4a and Oxazine 6a
a
Although intensive investigation on the mechanism is still
underway, we speculate that the reaction might initially involve
the attack of the Lewis basic sulfide activated Br (species B) by
the p-character σ-bond to give species C (Scheme 7). Since
excellent dr was obtained in the cyclization of the 1,2-trans-
substitued cyclopropane 5, we believe that species C, an
analogue of bromiranium ion A (Scheme 1, X = Br), might be
Scheme 7. Plausible Reaction Mechanism
a
Reactions were carried out with 5 (0.2 mmol), DBH (0.4 mmol), 4 Å
MS (250 mg), and Ph3PS (0.02 mmol) in (CH2Cl)2 (4 mL) at 25 °C
b
c
in the absence of light. 1.0 equiv of DBH was used. The reaction
time was 24 h.
excellent dr was obtained in all cases. The Br handle in 6 allows
for further modification flexibly. The relative stereochemistry of
6 was established on the basis of an X-ray crystallographic study
of a single-crystal sample of 6a.
Other than amide, carbamate was also found to be applicable
in this type of cyclization. When cyclopropylmethyl carbamate
7 subjected to the optimized conditions, cyclic carbamate 8 was
furnished in good yield (Scheme 5). One equivalent of water
was required for high reaction conversion, presumably for the
hydrolysis of the imine intermediate.
Scheme 5. Bromocyclization of Cyclopropylmethyl
Carbamate 7
The bromide in 4a and 6a could easily be substituted by
acetate followed by hydrolysis to give 9 and 10, respectively.
On the other hand, it is well-known that oxazolines and
oxazines could readily be opened to furnish the corresponding
1,2- and 1,3-amino alcohol systems.9 For instance, treatment of
oxazoline 4a with 1.5 M aqueous HCl under reflux gave the
corresponding 1,2-amino alcohol. It was found that the Br in 4a
was substituted by a water molecule simultaneously in the
reaction. Subsequent selective protection of the primary alcohol
yielded 11. These chemical operations provide a convenient
access to various pharmaceutically valuable substituted amino
alcohols (Scheme 6).
C
DOI: 10.1021/acs.orglett.5b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Klobukowski, M.; McDonald, R.; Santarsiero, B. D. J. Am. Chem. Soc.
1994, 116, 2448. (c) Neverov, A. A.; Brown, R. S. J. Org. Chem. 1996,
61, 962. (d) Olah, G. A.; Westerman, P. W. E.; Melby, G.; Mo, Y. K. J.
Am. Chem. Soc. 1974, 96, 3565. (e) Olah, G. A.; Bollinger, J. M.; Mo,
Y. K.; Brinich, J. M. J. Am. Chem. Soc. 1972, 94, 1164.
(3) De Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809.
(4) (a) Zhao, H.; Fan, X.; Yu, J.; Zhu, C. J. Am. Chem. Soc. 2015, 137,
3490. (b) Ren, S.; Feng, C.; Loh, T.-P. Org. Biomol. Chem. 2015, 13,
5105. (c) Kim, J.; Sim, M.; Kim, N.; Hong, S. Chem. Sci. 2015, 6, 3611.
(d) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137,
2042. (e) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.;
Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642. (f) Jiao, L.; Yuan, C.;
Yu, Z.-X. J. Am. Chem. Soc. 2008, 130, 4421.
configurationally stable as evidenced by the excellent dr of the
reaction (Scheme 4). The reaction was also found to be
enantiospecific when enantioenriched 5b (60% ee) was used. In
addition, the reaction efficiency diminished significantly when
the phenyl substituents of cyclopropanes were replaced by
aliphatic alkyl groups (5f or 3t) or the highly electron-deficient
4-nitrophenyl group (3u), which is similar to the general
reaction tendency in electrophilic bromination of olefins
observed by our group recently.10 Nucleophilic substitution
of C by the amide in an SN2 manner could yield the
Markovnikov-selective product 6. Alternatively, the reaction
might proceed through the carbocation intermediate C′, a ring-
opening species of C, followed by a rapid trapping of the
carbocation by the amide nucleophile intramolecularly to give
6.
(5) Zyk, N. V.; Gavrilova, A. Y.; Bondarenko, O. B.; Mukhina, O. A.;
Tikhanushkina, V. N. Russ. J. Org. Chem. 2011, 47, 340.
(6) An example on the use of cyclopropane in bromocyclization was
reported when we submitted this manuscript. For reference, see:
In summary, we have developed an efficient and diaster-
eoselective electrophilic bromocyclization of cyclopropylmethyl
amides catalyzed by triphenylphosphine sulfide. The oxazoline
and oxazine products could be transformed into biologically
valuable amino alcohol systems.
Rosner, C.; Hennecke, U. Org. Lett. 2015, 17, 3226.
̈
(7) (a) Colomer, I.; Adeniji, O.; Burslem, G. M.; Craven, P.;
Rasmussen, M. O.; Willaume, A.; Kalliokoski, T.; Foster, R.; Marsden,
S. P.; Nelson, A. Bioorg. Med. Chem. 2015, 23, 2736. (b) Xu, Z.; Tice,
C. M.; Zhao, W.; Cacatian, S.; Ye, Y.-J.; Singh, S. B.; Lindblom, P. B.;
Mckeever, M.; Krosky, P. M.; Kruk, B. A.; Berbaum, J.; Harrison, R. K.;
Johnson, J. A.; Bukhtiyarov, Y.; Panemangalore, R.; Scott, B. B.;
McGeehan, G. M.; Zhuang, L.; He, W.; Claremon, D. A. J. Med. Chem.
ASSOCIATED CONTENT
* Supporting Information
■
S
2011, 54, 6050. (c) Cochi, A.; Me
Org. Lett. 2010, 12, 3693.
́
tro, T. X.; Pardo, D. G.; Cossy, J.
Experimental procedures and characterization data for all new
compounds, and CIF file of the X-ray structure. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02557.
(8) (a) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355.
(b) Bode, H. B.; Irschik, H.; Wenzel, S. C.; Reichenbach, H.; Muller,
̈
R.; Hofle, G. J. Nat. Prod. 2003, 66, 1203. (c) Ghosh, A. K.;
̈
Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
(d) Lee, S. S.; Hadinoto, S.; Ying, J. Y. Adv. Synth. Catal. 2006, 348,
1248. (e) Wipf, P. Chem. Rev. 1995, 95, 2115.
X-ray data for compound 6a (CIF)
Experimental procedures and characterization data for all
new compounds (PDF)
(9) (a) Cahard, E.; Male, H. P. J.; Tissot, M.; Gaunt, M. J. J. Am.
Chem. Soc. 2015, 137, 7986. (b) Morse, P. D.; Nicewicz, D. A. Chem.
Sci. 2015, 6, 270. (c) Alhalib, A.; Kamouka, S.; Moran, W. J. Org. Lett.
2015, 17, 1453. (d) Jaganathan, A.; Borhan, B. Org. Lett. 2014, 16,
3616. (e) Cahard, E.; Bremeyer, N.; Gaunt, M. J. Angew. Chem., Int. Ed.
2013, 52, 9284. (f) Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am.
Chem. Soc. 2012, 134, 11980. (g) Jaganathan, A.; Garzan, A.;
Whitehead, D. C.; Staples, R. J.; Borhan, B. Angew. Chem., Int. Ed.
2011, 50, 2593. (h) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth.
2009, 86, 181.
(10) (a) Tay, D. W.; Leung, G. Y. C.; Yeung, Y.-Y. Angew. Chem., Int.
Ed. 2014, 53, 5161. (b) Zhao, Y.; Jiang, X.; Yeung, Y.-Y. Angew. Chem.,
Int. Ed. 2013, 52, 8597. (c) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng,
J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492. (d) Jiang, X.;
Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51,
7771. (e) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc.
2011, 133, 9164. (f) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung,
Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yyyeung@cuhk.edu.hk, chmyyy@nus.edu.sg.
Author Contributions
§Y.-C.W. and Z.K. contributed equally to this project.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from The Chinese
University of Hong Kong Startup Funding and National
University of Singapore Tier 1 Funding (Grant No. 143-000-
605-112).
REFERENCES
■
(1) For selected references of electrophilic bromination catalyzed by
Lewis basic chalcogens, see: (a) Kawato, Y.; Kubota, A.; Ono, H.;
Egami, H.; Hamashima, Y. Org. Lett. 2015, 17, 1244. (b) Ke, Z.; Tan,
C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627.
(c) Sawamura, Y.; Nakatsuji, H.; Sakakura, A.; Ishihara, K. Chem. Sci.
2013, 4, 4181. (d) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc.
2013, 135, 1232. (e) Balkrishna, S. J.; Prasad, C. D.; Panini, P.; Detty,
M. R.; Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541. (f) Snyder,
S.; Treitler, A. D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303.
(g) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U. S. A. 2010,
107, 20655. (h) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed.
2009, 48, 7899. (i) Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004,
69, 8979.
(2) (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131. (b) Brown, R. S.
R.; Nagorski, W.; Bennet, A. J.; McClung, R. E. D.; Aarts, G. H. M.;
D
DOI: 10.1021/acs.orglett.5b02557
Org. Lett. XXXX, XXX, XXX−XXX