DABCO: An efficient organocatalyst in the ring-opening reactions of aziridines with amines or thiols

Article abstract of DOI:10.1002/ejoc.200500576

Efficient ring-opening of aziridines with various amines or thiols catalyzed by DABCO afforded the corresponding products in good to excellent yields under mild reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500576

SHORT COMMUNICATION
DABCO: An Efficient Organocatalyst in the Ring-Opening Reactions of
Aziridines with Amines or Thiols
Jie Wu,*[a,b] Xiaoyu Sun,[a] and Yizhe Li[a]
Keywords: Organocatalysis / Aziridines / Ring opening
Efficient ring-opening of aziridines with various amines or
thiols catalyzed by DABCO afforded the corresponding pro-
ducts in good to excellent yields under mild reaction condi-
tions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
The interest in the field of organocatalysis has increased to effect the reaction.[9] Moreover, varied reaction condi-
spectacularly in the last few years as result of both the nov- tions were needed for various aziridines because of the dif-
elty of the concept and, more importantly, the fact that the ferent reactivity of substrates and reagents, as well as the
efficiency and selectivity of many organocatalytic reactions complexity of the structure of aziridines.[10–12] Recently,
meet the standards of established organic reactions. The di- Hou developed nonmetallic catalyzed ring-opening reac-
verse examples show that in recent years organocatalysis tions of aziridines with nucleophiles by utilizing tributyl-
has developed within organic chemistry into its own subdis- phosphane as catalyst, which opens the way to a variety of
cipline, whose “Golden Age” has already dawned.[1] The 1,2-bifunctional products.[13] However, the catalyst, Bu3P, is
pinpointing of “privileged” catalyst classes (such as l-pro- not stable and easy to be oxidized in the air. Furthermore,
line in aldol and Mannich reactions) showing general supe- high loading catalyst (at least 10%) had to be utilized in
riority for many reaction types is undoubtedly one of the order to achieve the respective yields. The yield and rate
most intriguing aspects and may have a considerable impact was dramatically decreased if catalyst loading was reduced.
on the development of new catalytic systems.[2,3] Catalysts For example, in the reaction of aziridine 1a with thiophenol
of the same class may promote similar reactions or less in acetonitrile, 95% yield of the corresponding product was
closely related reactions. For example, chiral thiourea deriv- obtained after 4 hours at room temperature when 1.0 equiv-
atives and their analogues catalyze the hydrocyanation of alent of catalyst was employed. However, the reaction was
imines (Strecker reaction) as well as asymmetric Mannich retarded if catalyst loading was reduced (10 mol-% of Bu3P,
reactions.[4] Tertiary amines are another example of a privi- 36 hours, 90% yield; 2 mol-% of Bu3P, 56 hours, 30%
leged catalyst class. They are able to mediate an astonish- yield).[13]
ingly wide variety of transformations.[5,6] For instance,
In view of the stability and nucleophilic similarity,
DABCO and its analogues show high efficiency in Morita- DABCO should be a very attractive alternative due to its
Baylis–Hillman reactions[6] as well as cyanation of unique characteristics. Initial studies were performed by
ketones.[7] Recently, we found that it was also efficient as using DABCO (5 mol-%) as catalyst in the reaction of com-
catalyst in the ring-opening reactions of aziridines with pound 1a with thiophenol in different solvents (THF, tolu-
various nucleophiles, such as amines or thiols, which is dis- ene, MeCN, CH2Cl2, DMF) at room temperature. To our
closed herein.
delight, we observed the formation of the corresponding
Ring-opening reactions of aziridines with nucleophiles product 2a. Complete conversion and 95% isolated yield
provide a useful protocol in organic synthesis, and many was obtained after 3 hours when the reaction was per-
reagents have recently been developed to realize the opening formed in MeCN. (Scheme 1) Further study showed that
of the aziridine ring.[8] However, most of these suffered 1 mol-% of catalyst was also efficient in this reaction at the
from the fact that a Lewis acid or strong base was necessary
[a] Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433, China
Fax: +86-21-6510-2412
E-mail: jie_wu@fudan.edu.cn
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Scheme 1. Reaction of 1a with thiopenol catalyzed by DABCO
(5 mol-%).
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032, China
Eur. J. Org. Chem. 2005, 4271–4275
DOI: 10.1002/ejoc.200500576
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J. Wu, X. Sun, Y. Li
SHORT COMMUNICATION
Table 1. Ring-opening reactions of aziridines with nucleophiles catalyzed by DABCO.
[a] Isolated yield based on aziridine. [b] Reaction was performed under reflux condition. [c] Absence of DABCO.
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Organocatalytic Ring-Opening Reactions of Aziridines
SHORT COMMUNICATION
expense of reaction time (6 h, room temp., 94% yield). It is activity of aziridine was reduced according to the decreased
noteworthy that this reaction could be run under the air electron-withdrawing ability of the substituent on the nitro-
without loss of efficiency. The anti-stereochemistry of the gen atom of aziridine. When 1g was employed in the reac-
product 2a was confirmed by the coupling constant for two tion with thiophenol (entry 19), the reaction time was ex-
cyclic methine hydrogens at the trans-positions.[11e,12d] We tended to 16 hours comparing to substrate 1a. Further
also screened other tertiary amines (Et3N, IPDEA, DBU, studies established showed that amines were also good nu-
DMAP, and quinuclidine) as organocatalyst in the reaction cleophiles by utilizing DABCO as catalyst although the re-
of 1a with thiophenol. It was found that DABCO was the action temperature should be elevated. (Table 1) In most of
best of choice.
the cases, reactions of aziridines with aromatic and aliphatic
To demonstrate the generality of this method, we next amines were all performed smoothly to afford the corre-
investigated the scope of this reaction and the results are sponding product in good to excellent yields. Due to the
summarized in Table 1. The operation is simple: thiol steric effect, lower yield (41%) of product 2h was obtained
(1.1 equiv.) was added to a solution of substrate 1 after 56 hours when 2,4,6-trimethylaniline was employed as
(0.25 mmol) (Figure 1) and DABCO (5 mol-%) in MeCN substrate. (entry 8) Regioselectivities were similar to those
(2.0 mL). The reaction mixture was stirred at room tem- described in the ring opening reaction with thiols. Other
perature for a period of time indicated in Table 1. After the nucleophiles, such as phenol, alcohol, benzoic acid, di-
reaction was completed monitored by TLC, the mixture was methyl malonate, were also employed in the reaction of 1a
separated directly by flash chromatography column (silica with expect to expand the scope of this reaction. However,
gel) to afford the corresponding product (Scheme 2).
only trace amount of product was detected even the reac-
tion was performed at reflux condition when phenol,
alcohol, or dimethyl malonate was used. (Table 1, entries
21–23) Reaction of p-methoxybenzoic acid with aziridine
1a performed smoothly and 73% yield of the desired pro-
duct was afforded (Table 1, entry 24).
What is the role of DABCO in this reaction? When aziri-
dine 1a was mixed with 1.0 equiv. of DABCO in acetonitrile
at room temperature, a white precipitate was formed after
several hours. After isolation, the structure of this expected
ammonium salt A was confirmed by 1H and 13C NMR
spectroscopy. This revealed that DABCO played a role as
nucleophile, and the attack of DABCO on aziridine to form
a ammonium salt is most likely the first step of the reaction.
When intermediate A was directly employed as catalyst in
the reaction of 1a and thiophenol, no displacement product
cis-2a was observed and the desired product trans-2a was
generated in 80% yield after 3 hours (Scheme 3).
Figure 1. Aziridine substrates 1.
Scheme 2. Reactions of aziridine 1 with nucleophiles catalyzed by
DABCO (5 mol-%).
The conditions have proved to be useful for coupling a
range of aziridines 1 with an array of thiols (Table 1). For
reactions of compounds 1a, various thiols are suitable sub-
strates. Both electron-rich and electron-poor thiophenols
gave similar yields. The reactions were very clean and the
desired products were afforded in good yields. Aliphatic
mercaptans were also good partners in this reaction. Usu-
ally, aromatic nucleophiles had higher reactivity than ali-
phatic ones. For example, reaction with thiophenol was fin-
ished in 3 hours (95% yield, entry 1). However, prolonged
reaction time (24 h) and higher temperature (under reflux)
were needed when benzyl mercaptan was used as nucleo-
Scheme 3. Reaction of 1a with thiophenol triggered by intermedi-
ate A.
Moreover, Hou pointed out that deprotonated product
phile (68% yield, entry 4). In the case of unsymmetrically of 2i, can also catalyze the reaction of 1a with BnSH.[13]
substituted aziridines 1c and 1d, completely regioselectivity According to these experimental facts, a possible mecha-
with the attack of nucleophile on the less substituted azirid- nism can be proposed (Scheme 4). DABCO attacks the azir-
ine carbon was observed. For the substrates 1f, as pre- idine to form a ammonium intermediate a, which could de-
viously reported, the attack of nucleophile was on the ben- protonate NuH to form intermediate b and Nu–. Then Nu–
zyl position due to electron effect. And also, it is reasonable reacts with aziridine to give the ring-opened intermediate c,
that regioselectivity is not as specific as others when azirid- which reacts with another NuH to provide the product 2
ine 1e was employed as the substrate. Furthermore, The re- and regenerate the Nu– to complete the catalytic cycle. The
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J. Wu, X. Sun, Y. Li
SHORT COMMUNICATION
Scheme 4. Possible mechanism.
1 H), 6.48–6.50 (d, J = 7.8 Hz, 2 H), 6.71–6.73 (t, J = 7.3 Hz, 1 H),
7.14–7.20 (m, 2 H), 7.25–7.30 (m, 2 H), 7.75 ppm (d, J = 8.2 Hz, 2
H).
tertiary amine acts as a nucleophilic trigger to produce in-
termediate a, which serves as a base to deprotonate the nu-
cleophile. Although the mechanism is not clear which need
more evidences to support, the role of tertiary amine as
base could not be excluded in this reaction. Details of the
mechanism is investigated now.
Acknowledgments
In summary, we have discovered DABCO was an ef-
ficient catalyst in the reactions of aziridines with amines or
thiols, which provided a general and convenient way to pre-
pare a variety of 1,2-diamines and 1,2-aminothioethers. The
advantages of this method include good substrate general-
ity, the use of air-stable, inexpensive DABCO as catalyst
under mild conditions, and experimentally operational ease.
Mechanism studies and desymmetrization of meso-azirid-
ines with various nucleophiles by using chiral tertiary
amines as catalysts are under investigation in our labora-
tory.
Financial support from Fudan University is gratefully acknowl-
edged.
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Experimental Section
General Procedure for the Reaction of Aziridines 1 with Thiols or
Amines: The thiol or amine (1.1 equiv.) was added to a solution of
substrate
1 (0.25 mmol) and DABCO (5 mol-%) in MeCN
(2.0 mL). The reaction mixture was stirred at room temperature
(thiols) or under reflux (amines) for a period of time indicated in
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˜
max
3265 cm–1. H NMR (500 MHz, [D6]DMSO): δ = 1.20–1.50 (m, 4
H), 1.50–1.75 (m, 2 H), 2.00–2.10 (m, 1 H), 2.20–2.30 (m, 1 H),
2.45 (s, 3 H), 3.00 (t, J = 11.4, 3.8 Hz, 1 H), 3.10 (dt, J = 11.1,
3.7 Hz, 1 H), 7.10–7.30 (m, 7 H), 7.63 (d, J = 8.2 Hz, 2 H), 7.80
ppm (d, J = 7.5 Hz, 1 H). EIMS: 361 (M+); C19H23NO2S2 (361.5):
calcd. C 63.13, H 6.41, N 3.87; found C 63.07, H 6.48, N 3.91%.
1
4-Methyl-N-[2-(phenylamino)cyclohexyl]benzenesulfonamide (2e):[13]
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(m, 1 H), 2.15–2.18 (m, 1 H), 2.45 (s, 3 H), 2.92 (dt, J = 10.0,
3.7 Hz, 1 H), 3.07 (dt, J = 10.1, 3.7 Hz, 1 H), 5.03 (d, J = 5.5 Hz,
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Organocatalytic Ring-Opening Reactions of Aziridines
SHORT COMMUNICATION
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Received: July 29, 2005
Published Online: August 29, 2005
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4275