Dimethylzinc-Mediated Chlorolactamization of Homoallylic Amines with Chloroform

Article abstract of DOI:10.1002/ejoc.201501241

A novel chlorolactamization reaction of homoallylic amines has been developed. The treatment of homoallylic amines with dimethylzinc in chloroform led to the formation of the corresponding β-chlorolactams via the Prins-type cyclization of a carbamoyl chlo

Full text of DOI:10.1002/ejoc.201501241

DOI: 10.1002/ejoc.201501241
Communication
Lactam Synthesis
Dimethylzinc-Mediated Chlorolactamization of Homoallylic
Amines with Chloroform
Yuika Nishida,[a] Masafumi Ueda,*[a] Masataka Hayashi,[a] Norihiko Takeda,[a] and
Okiko Miyata*[a]
Abstract: A novel chlorolactamization reaction of homoallylic tion of a carbamoyl chloride intermediate. The results of this
amines has been developed. The treatment of homoallylic
amines with dimethylzinc in chloroform led to the formation of
the corresponding β-chlorolactams via the Prins-type cycliza-
study highlight the synthetic utility of chloroform as a source
of both carbonyl group and chloride anion.
Introduction
As a preliminary experiment, we investigated the addition of
a trichloromethyl radical to the spirocyclic tetrahydroquinoline
3a [Scheme 1, Equation (2)]. Surprisingly, the reaction of 3a
with triethylborane[5] in chloroform gave the bridged lactam 5a
bearing a chloro group as a major product, along with a small
amount of the expected trichloromethylated product 4a.
Lactams are important structural units that can be found in a
broad range of compounds, including natural products,[6] bio-
logically active compounds[7] and functional materials.[8] Hence,
the development of practical synthetic strategies for the con-
struction of lactams has attracted considerable attention.[9] De-
spite extensive progress in this area, the development of effi-
cient methods for the preparation of bridged lactams is still
highly desired.[10] With this in mind, the interesting result de-
scribed above could provide an alternative approach for the
preparation of bridged lactams and lead to the advance of syn-
thetic chemistry. Herein, we report the development of a novel
chlorolactamization reaction of homoallylic amines using
chloroform as a C1 carbon source.
The trichloromethyl group is a valuable functional group in or-
ganic synthetic chemistry, because it can be readily converted
into a wide range of different functionalities.[1] Based on the
importance and synthetic utility of this group, considerable re-
search efforts have been directed towards the development of
efficient trichloromethylation reactions.[2] We recently devel-
oped a reaction for the direct addition of chloroform to cyclo-
propenes. This reaction proceeded through the generation of a
trichloromethyl radical, which was formed by the triethyl-
borane-mediated cleavage of the C–H bond of chloroform
[Scheme 1, Equation (1)].[3] We envisaged that this reaction
could be applied to the synthesis of functionalized spiro hetero-
cycles, some examples of which can be found in a variety of
interesting biologically active compounds.[4]
Results and Discussion
We initially conducted a screening process to identify the opti-
mal conditions for the chlorolactamization of 3a (Table 1).
When dimethylzinc[11] (8 equiv.) was used as a radical initia-
tor instead of triethylborane in the presence of air, the bicyclic
lactam 5a was formed exclusively in 86 % yield. The ratio of the
1
stereoisomers was determined by H NMR spectroscopy to be
3:1 in favor of the endo isomer (Table 1, Entry 2). The reaction
with diethylzinc also gave 5a as the sole product, albeit in a
much lower yield (Table 1, Entry 3). Decreasing the amount of
dimethylzinc to 4 equiv. resulted in a significant reduction of
the yield of the desired product (Table 1, Entry 4). Several other
solvents were also screened against this reaction, including
carbon tetrachloride and dichloromethane. Disappointingly,
however, both of these solvents displayed rather poor reactivity,
indicating that chloroform played an important role in this
lactamization reaction (Table 1, Entries 5 and 6). Dioxygen was
Scheme 1. Addition reactions of a trichloromethyl radical.
[a] Kobe Pharmaceutical University
Motoyamakita, Higashinada, Kobe 658-8558, Japan
E-mail: masa-u@kobepharma-u.ac.jp (M. U.)
miyata@kobepharma-u.ac.jp (O. M.)
http://www.kobepharma-u.ac.jp/english/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501241.
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Communication
Table 1. Optimization of the reaction conditions.[a]
Several control experiments were conducted to elucidate the
mechanism of this reaction. Interestingly, the application of the
optimized reaction conditions to spirotetraline 6, which has no
nitrogen atom, resulted in no reaction, with the starting mate-
rial 6 being recovered quantitatively [Scheme 2, Equation (3)].
In contrast, spirotetrahydroquinoline 7, which does not contain
an alkene moiety, gave the urea and acetamide derivatives 8
and 9 in 64 and 28 % yields, respectively [Scheme 2, Equa-
tion (4)]. These results suggested that the carbonylation of the
amino group was one of the initial steps in the lactamization
reaction. It is noteworthy that the trichloromethylated spiro-
quinoline 4a was not involved as an intermediate in the chloro-
lactamization reaction, since the treatment of 4a with dimethyl-
zinc in chloroform did not produce any of the desired lactam
5a but gave the acetamide 10 in low yield [Scheme 2, Equa-
tion (5)]. We then treated 3a with triphosgene instead of di-
methylzinc. Interestingly, the chlorolactam 5a was obtained in
65 % yield, indicating that the carbamoyl chloride derivative of
3a would be generated as a key intermediate in the chloro-
lactamization reaction [Scheme 2, Equation (6)].[12]
Entry
Radical initiator
(equiv.)
Solvent
Yield [%]
5a[b]
4a
1
2
3
4
5
Et3B (8)
CHCl3
CHCl3
CHCl3
CHCl3
CCl4
40
86
36
26
3
12
–
–
–
–
Me2Zn (8)
Et2Zn (8)
Me2Zn (4)
Me2Zn (8)
Me2Zn (8)
Me2Zn (8)
6
CH2Cl2
CHCl3
–
–
7[c]
n.r.[d]
[a] All of these reactions were performed with 3a (0.3–0.5 mmol) at a 0.1
M
concentration. [b] The ratio of stereoisomers was in the range of 1:1–3:1 de-
termined by 1H NMR analysis. [c] The reaction was carried out under strictly
deoxygenated conditions. [d] n.r.: no reaction.
found to be essential for this transformation, because no reac-
tion occurred under strictly deoxygenated conditions (Table 1,
Entry 7).
With the optimized conditions in hand, we proceeded to in-
vestigate the effects of different substituents on the benzene
ring (Table 2, Entries 1–3). The results revealed that the pres-
ence of an electron-donating group on the benzene ring (e.g.,
methoxy or methyl) was well tolerated, with the corresponding
lactams 5b and 5c being formed in moderate yields (Table 2,
Entries 1 and 2). The presence of a chloro substituent on the
benzene ring was also well tolerated by the reaction (Table 2,
Entry 3). The effect of the ring size of the heterocycle was also
examined. Pleasingly, indoline 3e bearing a cyclopentenyl
group at its 2-position reacted smoothly to give the desired
lactam 5e in excellent yield (Table 2, Entry 4). Furthermore, this
reaction was found to be amenable to larger heterocyclic ring
systems, including the corresponding azepine and azocine sys-
tems (Table 2, Entries 5 and 6).
Table 2. Reactions of various cyclopentenylamines with Me2Zn and CHCl3.
Scheme 2. Elucidation of the reaction pathway.
Based on the results of the control experiments described
above, we propose a plausible mechanism for this chloro-
lactamization reaction, which is shown in Scheme 3. The methyl
and methoxy radicals generated by the oxidative decomposi-
tion of dimethylzinc would initially abstract a hydrogen atom
from chloroform to form the corresponding trichloromethyl
radical [Scheme 3, (1)]. This radical would subsequently react
with molecular oxygen and dimethylzinc to form phosgene
[Scheme 3, (2)].[13] The acylation of zinc amide A with phosgene
would give carbamoyl chloride B. The subsequent elimination
of a chloride anion from B by dimethylzinc would lead to the
formation of the acylium ion C, which would undergo an intra-
molecular Prins-type cyclization[14] with the introduction of a
chloro atom to give the bridged lactam 5a [Scheme 3, (3)].[15]
Entry
Substrate
R1
R2
n
Product
Yield [%][b]
1
2
3
3b
3c
3d
3e
3f
MeO
H
Cl
H
H
H
Me
H
H
H
1
1
1
0
2
3
5b
5c
5d
5e
5f
67
54
62
95
68
60
4[a]
5
6
3g
H
H
5g
[a] Me2Zn (4 equiv.) was used as the radical initiator. [b] The ratio of stereoiso-
mers was in the range of 1:1–4:1 determined by 1H NMR analysis.
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It should be noted that chloroform acted not only as a source cyclic moiety, both reacted well under the optimized conditions
of a carbonyl group in this reaction but that it also provided a to give the corresponding lactams 12a and 12b [Scheme 4,
chloride anion.[16]
Equation (7)]. This 2-azabicyclo[2.2.1]heptanone skeleton can be
used for the synthesis of various biologically active com-
pounds.[10b] Furthermore, these results suggested that our
newly developed chlorolactamization reaction had a broad sub-
strate scope. Indeed, the acyclic homoallylic amines 13a and
13b were also converted into the corresponding dihydropyrid-
inones 14a and 14b by a dimethylzinc-mediated chlorolactam-
ization followed by the DBU-mediated elimination of HCl
[Scheme 4, Equation (8)]. This suggested that the cyclization
would not involve the intramolecular addition of the carbamoyl
radical to alkenes.[17] The reactions of internal alkenes were also
investigated [Scheme 4, Equations (9) and (10)]. For example,
the chlorolactamization and elimination reaction of 15 bearing
a benzyl group at its alkene terminus gave the desired six-mem-
bered lactam 16 in moderate yield. It is noteworthy that the
five-membered lactam 18 was formed exclusively when 17
bearing a phenyl group at its alkene terminus was allowed to
react under the optimized conditions, most likely because of
the high stability of the resulting benzyl cation.
Conclusions
We have developed a novel chlorolactamization reaction of
homoallylic amines that is initiated by the generation of a tri-
chloromethyl radical from chloroform and dimethylzinc. The re-
sults of this study have shown that chloroform can be used as
a source of carbonyl group and chloride anion. Efforts to further
expand upon the scope of this reaction, clarify the reaction
mechanism and demonstrate the synthetic utility of the pro-
ducts are currently underway in our laboratory.
Scheme 3. Plausible reaction pathway.
To confirm the generality of this chlorolactamization reac-
tion, we conducted some additional experiments to expand on
the substrate scope of this transformation (Scheme 4). Cyclo-
pentenylamines 11a and 11b, which did not contain a spiro-
Experimental Section
Representative Procedure for the Chlorolactamization of Ho-
moallylic Amine 3a: Compound 3a (92.3 mg, 0.5 mmol) was dis-
solved in CHCl3 (5.0 mL) under air. The flask was fitted with a nitro-
gen balloon. Me2Zn (1.0
M in hexane, 1.0 mL, 1.0 mmol) was added
4 times at 2 h intervals to the solution of 3a in CHCl3 with stirring
at room temperature. After being stirred at the same temperature
for 24 h, the reaction mixture was diluted with satd. aq. NH4Cl solu-
tion and extracted with CHCl3. The organic phase was dried with
MgSO4 and concentrated under reduced pressure. Purification of
the residue by preparative TLC (n-hexane/AcOEt, 5:1) afforded endo-
5a (80.5 mg, 65 %) and exo-5a (25.8 mg, 21 %).
Acknowledgments
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT), the MEXT-Supported Program for the Strategic Re-
search Foundation at Private Universities, and the Takeda Sci-
ence Foundation.
Keywords: Alkenes · Chloroform · Heterocycles · Lactams ·
Radicals
Scheme 4. Scope of the chlorolactamization reaction.
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Received: September 28, 2015
Published Online: December 7, 2015
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