Effect of halogenation reagents on halocyclization and Overman rearrangement of allylic trichloroacetimidates

Article abstract of DOI:10.1016/j.tetlet.2011.09.057

Electrophilic halogen can promote either halocyclization or Overman rearrangement of allylic trichloroacetimidates. We found that the chemoselectivity was dependent on the nature of the halogenation reagents for primary allylic trichloroacetimidates. A one-pot procedure was developed for the preparation of allylic trichloroacetamides directly from allylic alcohols at room temperature.

Full text of DOI:10.1016/j.tetlet.2011.09.057

Tetrahedron Letters 52 (2011) 6217–6219
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effect of halogenation reagents on halocyclization and Overman
rearrangement of allylic trichloroacetimidates
⇑
Na Liu, Casi M. Schienebeck, Michelle D. Collier, Weiping Tang
School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrophilic halogen can promote either halocyclization or Overman rearrangement of allylic trichloro-
acetimidates. We found that the chemoselectivity was dependent on the nature of the halogenation
reagents for primary allylic trichloroacetimidates. A one-pot procedure was developed for the prepara-
tion of allylic trichloroacetamides directly from allylic alcohols at room temperature.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 August 2011
Revised 10 September 2011
Accepted 13 September 2011
Available online 19 September 2011
Keywords:
Overman rearrangement
Halocyclization
Allylic alcohols
Allylic amide
Halogen
The [3,3]-sigmatropic rearrangement of allylic trichloroacetim-
idate 2 (Overman rearrangement) has been widely used for the
preparation of protected allylic amine 3 from allylic alcohol 1
(Scheme 1).1–3 The thermal and Hg(II)-catalyzed process was first
reported by Overman in 1974.4 The same group also developed
the enantioselective process for the rearrangement of primary
allylic trichloroacetimidate 2 employing a chiral Pd(II) catalyst.5
Metal complexes including Hg(II), Pd(II), Pt(II), Pt(IV), Au(I), and
Au(III) salts can lower the temperature required for the rearrange-
ment of allylic trichloroacetimidates and allow the reaction to be
carried out at room temperature or lower.1,4,6
It has been reported that N-bromosuccinimide (NBS) or N-iodo-
succinimide (NIS) could promote Overman rearrangement if R1 in
trichloroacetimidate 2 is an electron withdrawing group such as
phosphonate or cyano groups.7 The proposed mechanism of this
halogen-promoted Overman rearrangement is shown in Scheme
1.7 On the other hand, numerous examples of halogen-promoted
halocyclization of allylic trichloroacetimidates were also known.8
The occurrence of the unusual halogen-promoted Overman rear-
rangement was attributed to the electron withdrawing R1 substitu-
ent (phosphonate or cyano groups) in compound 2.7 We herein
report that primary allylic trichloroacetimidates (2, R1 = H) can also
undergo halogen-promoted Overman rearrangement at room tem-
perature in the presence of amine catalysts. The choice of electro-
philic halogenation reagents is critical for chemoselective Overman
rearrangement over halocyclization.
During our development of stereoselective halocyclization reac-
tions,9,10 we became interested in using trichloroacetimidates as
nitrogen nucleophiles. When allylic trichloroacetimidate 2a was
treated with NCS, no reaction was observed (Table 1, entry 1).
We9,10 and others11 have found that various catalysts can facilitate
the halogen-promoted cyclization or addition reactions. We then
screened different catalysts and halogenation reagents. Overman
rearrangement product 3a was isolated in 34% yield together with
50% of recovered 2a after 10 h in the presence of quinine catalyst
10 (entry 2). The yield of product 3a was improved to 76% using
1,3-dichloro-5,5-dimethylhydantoin (DCDMH) 9 as the halogena-
tion reagent and quinine 10 as the catalyst (entry 4). The yield of
product 3a dropped slightly with substoichiometric amount of hal-
ogen reagents (entry 5). DBU and catalyst 11 all provided lower
yields of product 3a (entries 6 and 7), indicating that the hydroxyl
CCl3
NH
CCl3
NH
thermal
or catalyst
catalytic DBU
Cl3CCN
OH
O
O
R1
R2
R1
R2
R1
R2
1
2
3
CCl3
CCl3
CCl3
NH
R2
NBS or
NIS
O
NH
R2
O
NH
R2
O
3
2
R1
R1
R1
X
X
X
5
6
4
⇑
Corresponding author. Tel.: +1 608 890 1846; fax: +1 608 262 5345.
E-mail address: wtang@pharmacy.wisc.edu (W. Tang).
Scheme 1. Overman rearrangement.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.057

6218
N. Liu et al. / Tetrahedron Letters 52 (2011) 6217–6219
Table 1
Table 2
Effect of halogen on Overman rearrangement and halocyclization of allylic
trichloroacetimidates
Preparation of allylic amides from allylic alcohols via halogen-promoted Overman
rearrangement in a one-pot procedure
CCl3
N
CCl3
CCl3
NH
nPr
CCl3
NH
nPr
OH
1. 10 mol % DBU, MS, CCl3CN, rt, 3h
2. 1.0 equiv DCDMH, rt, 24h
O
O
NH
O
O
conditions
and/or
R
nPr
R
1
X
3
2a
3a
7, X=Br
8, X=I
Entry
Structure of substrates
Yields
O
OMe
1
2
3
4
5
6
7
8
9
1a, R = nPr
1b, R = cHex
1c, R = Me
1d, R = PhCH2CH2
1e, R = Ph
1f, R = 4-ClC6H4
1g, R = 4-(NO2)C6H4
1h, R = 3-(NO2)C6H4
1i, R = 4-BrC6H4
1j, R = 2-BrC6H4
1k, R = 4-(CH3O)C6H4
1l, Cyclohex-2-en-1-ol
72%
78%
64%
54%
81%
59%
55%
53%
71%
62%
See text
NR
Cl
N
OMe
OMe
N
N
Cl
N
N
NH
O
N
OMe
OH
9
O
NH
Ts
N
N
DCDMH
12
11
10
Entry
Conditions
1.2 equiv NCS
1.2 equiv NCS, 10 mol % 10
1.2 equiv 9
1.2 equiv 9, 10 mol % 10
0.4 equiv 9, 10 mol % 10
1.2 equiv 9, 10 mol % DBU
1.2 equiv 9, 10 mol % 11
1.2 equiv 9, 10 mol % 12
1.2 equiv NBS
Yield of 3a
Yield of 7 or 8
10
11
12
1
2
3
4
5
6
7
8
9
No reaction
34%
No reaction
76%
67%
50%
50%
32%
No reaction
—
OH
—
—
13
NR
1m,
OMe
—
—
10
11
1.2 equiv NBS, 10 mol % 10
1.2 equiv NIS
73% yield of 3a and 7 (3a:7 = 1.4:1)
63% of 8
Our preliminary study showed that good yield and observable
enantioselectivity could be achieved for allylic amide 3e (Eq. 2).
This halogen-promoted process has the potential to become an
alternative metal-free approach for enantioselective Overman
rearrangement.
—
group in quinine 10 is beneficial for the reaction. Much lower con-
version was observed in the presence of chiral catalyst 12 (entry
8).10 Interestingly, an inseparable mixture of Overman rearrange-
ment product 3a and bromocyclization product 7 was observed
when NBS and quinine were used as the halogenation reagent
and catalyst respectively (entry 10). Treatment of 2a with NIS in
the absence of quinine yielded 6-endo-cyclization product 8 to-
gether with small amount of 5-exo-cyclization product (entry 11).
Since DBU is also the catalyst for the preparation of allylic tri-
chloroacetimidate 2 from the corresponding alcohol 1, we then
examined the one-pot procedure for the preparation of allylic
amides from allylic alcohols (Table 2). Allylic trichloroacetamide
3a can be directly prepared in 72% yield from allylic alcohol 1a
by sequential addition of trichloroacetonitrile and DCDMH in the
presence of 4 Å molecular sieves (MS) and a catalytic amount of
DBU (entry 1). We then explored the scope of this protocol for
the preparation of allylic trichloroacetamides. The reaction toler-
ated various alkyl and aryl substituted primary allylic alcohols (en-
tries 2–10).
CCl3
1.2 equiv DCDMH
10 mol % catalyst
O
NH
Ph
3e
DCM
ð2Þ
2e
ee
chiral catalysts:
catalyst 10
isolated yield
63%
<1%
10-13%
<1%
<1%
catalyst 11
72%
catalyst 12
44%
58%
(DHQD)2PHAL
In summary, we found that the chemoselectivity for halocycli-
zation or Overman rearrangement of allylic trichloroacetimidates
is highly dependent on the halogenation reagent. We demon-
strated, for the first time, that a halogen could promote Overman
rearrangement of trichloroacetimidates derived from primary
allylic alcohols. A one-pot procedure was developed for the prepa-
ration of allylic trichloroacetamides from primary allylic alcohols
at room temperature.
A complex mixture was obtained for substrate 1k, which has an
electron-rich aryl substituent. No rearrangement product was ob-
served for secondary cyclic or acyclic allylic alcohols 1l and 1m.
When DBU, trichloroacetonitrile, and DCDMH were added to-
gether to allylic alcohol 1e, product 3e could be isolated in 60%
yield (Eq. 1), which was lower than that obtained from sequential
additions as shown in Table 2 (entry 5). Under the identical condi-
tion shown in (Eq. 1), substrate 1a only yielded trace amounts of
rearrangement product and most of the starting material was
recovered. This suggested that the introduction of halogenation re-
agent in the first step was detrimental for substrates with an alkyl
substituent.
Acknowledgment
We thank University of Wisconsin-Madison for start up
funding.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.057.
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