[Pd(PPh3)4]-catalyzed diastereoselective synthesis of trans-1,2-diazetidines from 2,3-allenyl hydrazines and aryl halides

Article abstract of DOI:10.1002/anie.200800364

(Chemical Equation Presented) Strain, what strain? Pd⁰-catalyzed cyclization of easily accessed and diversely substituted 2,3-allenyl hydrazines with aryl halides afforded 1,2-diazetidines with two chiral centers in high regio- and diastereosel

Full text of DOI:10.1002/anie.200800364

Angewandte
Chemie
DOI: 10.1002/anie.200800364
Cyclizations
[Pd(PPh3)4]-Catalyzed Diastereoselective Synthesis of trans-1,2-
Diazetidines from 2,3-Allenyl Hydrazines and Aryl Halides**
Xin Cheng and Shengming Ma*
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Four-membered cyclic compounds are found in many biolog-
ically active natural and unnatural compounds.[1] Accessing
such compounds is a synthetic challenge for synthetic organic
chemists because of the intrinsic ring strain.[2] Diazetidines
are a type of four-membered ring, which contains two
nitrogen atoms, and can be dated back to the 1850ꢀs; however,
most of the early synthetic reports were later shown to be
incorrect.[3] In addition, the discovery of penicillin in 1929
stimulated ongoing interest in this type of structure from
physical, polymer, theoretical, and medicinal chemists. Nota-
bly, the methods for the synthesis of 1,2-diazetidines are
limited: (1) the [2+2] cycloaddition reaction of azodicarboxyl
compounds react only with the electron-rich olefins, lacking
allylic hydrogens, in very poor selectivity affording also the
six-membered [4+2] cycloaddition byproduct;[4] (2) the direct
bisalkylation of 1,2-dibromoethane with 1,2-dialkylhydra-
tetrahydropyridines albeit with poor selectivity. We recently
showed that the [Pd(PPh3)4]-catalyzed coupling/cyclization
reaction of nonsubstituted or 5-substituted-3,4-allenyl amides
with organic halides afforded a mixture of four- and six-
membered ring products, however, the selectivity and yield
for the formation of four-membered products were low.[13]
Herein, we describe a highly efficient regio- and diastereo-
selective synthesis of trans-1,2-diazetidines through the cyc-
lization reaction of 2,3-allenylic hydrazines with aryl halides.
In our initial attempt, we synthesized 2,3-allenylic hydra-
zine 1a[14] and chose [Pd(PPh3)4] as the catalyst. During
screening, it was observed that the reaction of 1a with 4-
iodotoluene in MeCN with Na2CO3 as the base afforded 1,2-
diazetidine 3a in 11% yield (Table 1, entry 1). Additional
Table 1: [Pd(PPh3)4]-catalyzed reaction of allenyl hydrazine 1a and 4-
iodotoluene under different reaction conditions.
zines afforded simple nonfunctionalized diazetidines in very
[5]
lowyield;
(3) the intramolecular cyclization of 1-(1-hy-
droxy-propan-2-yl)hydrazine-1,2-dicarboxylate derivatives
was reported by Ma and co-workers in 2006.[6] Thus, new
methods for a highly selective and high yielding synthesis of
functionalized 1,2-diazetidines are still of current interest.
Recently, there has been much attention focused on the
coupling/cyclization reaction of organic halides with function-
alized allenes for the synthesis of some potentially important
carbo- and heterocyclic compounds.[7–9] However, a highly
selective formation of four-membered rings still remains a
challenge; for example, Hiemstra and co-workers and
Tanaka, Ibuke, and co-workers, as well as Kang et. al.
reported the palladium-catalyzed coupling/cyclization reac-
tion of 3,4-dienyl amide derivatives with organic halides[10,11]
or hypervalent iodonium salts[12] to form azetidines and/or
Entry Base
t [h] Yield of
3a [%][a]
trans:cis ratioof
3a
Yield of
4a [%][a]
1
Na2CO3 24
11[b]
100:0
100:0
0
0
2
3
4
NaOH
KOBut
Et3N
5
2
20
n.d.
n.d.
5[c]
5
Cy2NMe 30.5 trace
6
7
8
9
Cs2CO3
Ag2CO3
K2CO3
CsF
2
2
6
24
2
2
74
53
74
64
59
77
100:0
100:0
20:1
17:1
100:0
100:0
<7
<10
trace
trace
<6
[*] X. Cheng, Prof. Dr. S. Ma
10
11
KOH
Cs2CO3
[d]
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-7510
<7
[a] Yield of isolated product. [b] Recovered 82% of 1a. [c] Recovered
87% of 1a. [d] Used 1.1 equiv of Cs2CO3. n.d.=not determined becasue
of complicated reaction mixture.
E-mail: masm@mail.sioc.ac.cn
[**] We greatly acknowledge financial support from the Major State
Basic Research Development Program (Grant No. G200077500),
National Natural Science Foundation of China (No. 20121202,
20332060, and 20423001), and Shanghai Municipal Committee of
Science and Technology. We thank Ping Lu in this group for
reproducing the results presented in Table 1 (entries 3, 8, and 14)
and Table 2 (entry 1).
studies indicated that NaOH, KOtBu, Et3N, and Cy2NMe
were poor bases for this reaction (Table 1, entries 2–5).
However, Cs2CO3, Ag2CO3, K2CO3, CsF, or KOH all provided
four-membered ring 3a in 53–74% yield (Table 1, entries 6–
10); the reaction with K2CO3 (Table 1, entry 8) or CsF
(Table 1, entry 9) provided the desired product with low
stereoselectivity. Thus, reaction conditions (Conditions A:
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 4581 –4583
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4581

Communications
Table 3: Diastereoselective synthesis of optically active vinylic 1,2-
diazetidines.
organic halide (1.2 equiv), [Pd(PPh3)4] (5 mol%), Cs2CO3
(1.1 equiv), MeCN, 808C) were defined as the optimal set of
conditions for the cyclization (Table 1, entry 11). Compound
3a was fully characterized by NMR, IR, MS, and HRMS
1
methods. From the H NMR spectrum the coupling constant
between the two methine protons is approximately 5.2 Hz,
which led to the assignment of a trans stereochemistry.[4a–c,f,h]
Careful analysis revealed that the yield for five-membered
ring regioisomer 4a is less than 7% when the optimal reaction
conditions were used.[15]
The scope of the diastereoselective 1,2-diazetidine-form-
ing reaction was then investigated by using the optimal
reaction conditions, and some of the results are listed in
Table 2. Noteworthy are: (1) in all the cases the diastereose-
lectivity is very high with only the trans-3 products being
formed, (2) the yields range from moderate to good.
Entry R1 ((S)-1)
R2 (2)
Yield of (3S,4S)-3 [%] ee [%][a]
1
2
3
4
n-C5H11 (1a) p-MeC6H4
74 (3a)
99.4
99.4
98.5
98.5
n-C5H11 (1a) p-MeOC6H4 74 (3d)
n-C7H15 (1b) p-MeC6H4 68 (3e)
n-C7H15 (1b) p-MeOC6H4 75 (3h)
[a] The ee values were determined by HPLC analysis (see the Supporting
Information).
diazetidines in good yields. By using the readily accessible
enantiomerically enriched 2,3-allenyl hydrazines, optically
active vinylic 1,2-diazetidines with high ee values can be
synthesized. Because of the importance of 1,2-diazetidines[18]
and the ready access to the starting materials, this reaction
will have applications in organic synthesis. Additional studies
in this area are being conducted in our laboratory.
Table 2: [Pd(PPh3)4]-catalyzed synthesis of trans-1,2-diazetidines by the
cyclization of 2,3-allenyl hydrazines with aryl halides.
R1 (1)
R2 (2)
Yield of 3 [%][a]
Experimental Section
Entry
Synthesis of 3a: Under an atmosphere of argon, Cs2CO3 (90 mg,
0.28 mmol), 4-iodotoluene (65 mg, 0.30 mmol), [Pd(PPh3)4] (15 mg,
0.013 mmol), 1a (76 mg, 0.25 mmol), and CH3CN (3 mL) were added
sequentially to an oven-dried Schlenk tube equipped with a stirring
bar. The reaction mixture was stirred at 808C for 2 h, at which time
the reaction was complete as determined by TLC analysis. The
resulting mixture was concentrated and the residue was purified by
flash chromatography on silica gel (petroleum ether/ether= 10:1) to
afford 7 mg of an unidentified mixture and 76 mg (77%) of 3a:
Liquid; 1H NMR (300 MHz, CDCl3): d = 7.23 (d, J = 8.3 Hz, 2H),
7.13 (d, J = 8.3 Hz, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 4.81 (d, J = 5.2 Hz,
1H), 4.34–4.17 (m, 4H), 3.85 (dt, J = 5.2 and 6.9 Hz, 1H), 2.33 (s, 3H),
1.86–1.62 (m, 2H), 1.33–1.12 (m, 12H), 0.81 ppm (t, J = 6.8 Hz, 3H);
13C NMR (75.4 MHz, CDCl3): d = 161.1, 160.6, 144.2, 137.9, 134.5,
129.1, 126.3, 113.7, 69.4, 69.1, 62.4, 62.2, 34.5, 31.2, 24.0, 22.3, 21.0,
14.3, 14.2, 13.8 ppm; MS (EI) m/z (%) 388 (M+, 23.29), 144 (100); IR
(neat) 2932, 1752, 1713, 1626, 1513, 1466, 1322, 1099 cmÀ1; HRMS
(EI) calcd for C22H32N2O4 [M+] 388.2362. Found 388.2365.
1
2
3
4
5
6
7
8
n-C5H11 (1a)
n-C5H11 (1a)
n-C5H11 (1a)
n-C5H11 (1a)
n-C7H15 (1b)
n-C7H15 (1b)
n-C7H15 (1b)
n-C7H15 (1b)
n-C8H17 (1c)
n-C8H17 (1c)
n-C8H17 (1c)
n-C8H17 (1c)
PhCH2 (1d)
PhCH2 (1d)
PhCH2 (1d)
PhCH2 (1d)
p-MeC6H4
m-MeC6H4
Ph
p-MeOC6H4
p-MeC6H4
m-MeC6H4
Ph
p-MeOC6H4
p-MeC6H4
m-MeC6H4
Ph
p-MeOC6H4
p-MeC6H4
m-MeC6H4
Ph
77 (3a)
71 (3b)
70 (3c)
73 (3d)
75 (3e)
70 (3 f)
63 (3g)
75 (3h)
72 (3i)
71 (3j)
66 (3k)
74 (3l)
68 (3m)
68 (3n)
62 (3o)
71 (3p)
9
10
11
12
13
14
15
16
p-MeOC6H4
[a] Yield of isolated product.
Received: January 24, 2008
Revised: March 9, 2008
Published online: May 6, 2008
By using the protocol for the diastereoselective synthesis
of trans-1,2-diazetidine, additional studies were conducted to
investigate the possibility of synthesizing optically active
trans-1,2-diazetidines. Optically pure (R)-1,2-nonadien-4-ol
and (R)-1,2-undecadien-4-ol were readily prepared by the
CrabbØ reaction of (R)-1-octyn-3-ol and (R)-1-decyn-3-ol,
respectively,[16] which are easily made from the kinetic
enzymatic resolution of the corresponding racemic propar-
gylic alcohols.[17] Optically active (S)-1 can be easily prepared
by the reaction of optically pure 2,3-allenols with diethyl
azodicarboxylate.[14] The reaction of optically active (S)-1a or
(S)-1b with aryl halides afforded optically active 1,2-diazeti-
dines (S,S)-3 diastereoselectively with high enantiopurities
(Table 3).
Keywords: allenes · cyclization · diastereoselectivity ·
.
heterocycles · palladium
[1] a) A. Pommier, J. M. Pons, Synthesis 1993, 441; b) A. Pommier,
J. M. Pons, Synthesis 1995, 729; c) Comprehensive Heterocyclic
Chemistry II (Eds.: A. R. Katritzky, C. W. Rees, E. F. V Scriven),
Pergamon, NewYork, 1996, chap. 1.18–1.39; d) The Chemistry
of b-lactams (Ed.: M. I. Page), Blackie Academic & Professio-
nal, NewYork, 1992; e) Chemistry and Biology of b-lactam
Antibiotics, Vol. 1–3 (Eds.: R. B. Morin, M. Gorman), Academic
Press, NewYork, 1982; f) W. Adam, G. Cilento, Angew. Chem.
1983, 95, 525; Angew. Chem. Int. Ed. Engl. 1983, 22, 529; g) F.
Toda, P. Garratt, Chem. Rev. 1992, 92, 1685; h) S. Robin, G.
Rousseau, Eur. J. Org. Chem. 2002, 3099.
In conclusion, we have developed a mild and highly
diastereoselective methodology for the synthesis of trans-1,2-
4582
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4581 –4583

Angewandte
Chemie
[2] a) R. D. Bach, O. Dmitrenko, J. Org. Chem. 2002, 67, 2588;
b) R. J. Cantlin, J. Drake, R. W. Nagorski, Org. Lett. 2002, 4,
2433; c) T. Hamura, Y. Ibusuki, K. Sato, T. Matsumoto, Y.
Osamura, K. Suzuki, Org. Lett. 2003, 5, 3551; d) T. Dudev, C.
Lim, J. Am. Chem. Soc. 1998, 120, 4450; e) A. Greer, F. Jensen,
E. L. Clennan, J. Org. Chem. 1996, 61, 4107; f) J. Fleischhauer, R.
Beckert, W. Günther, H. Görls, Synthesis 2006, 2885; g) A.
Padwa, G. D. Kennedy, M. W. Wannamaker, J. Org. Chem. 1985,
50, 5334; h) A. Padwa, M. Pulwer, J. Am. Chem. Soc. 1980, 102,
6386.
Angew. Chem. Int. Ed. 2006, 45, 1426; g) N. Morita, N. Krause,
Angew. Chem. 2006, 118, 1930; Angew. Chem. Int. Ed. 2006, 45,
1897; h) N. Nishina, Y. Yamamoto, Angew. Chem. 2006, 118,
3392; Angew. Chem. Int. Ed. 2006, 45, 3314; i) H. Guo, Z. Zheng,
F. Yu, S. Ma, A. Holuigue, D. S. Tromp, C. J. Elsevier, Y. Yu,
Angew. Chem. 2006, 118, 5119; Angew. Chem. Int. Ed. 2006, 45,
4997; j) R. L. Lalonde, B. D. Sherry, E. J. Kang, F. D. Toste, J.
Am. Chem. Soc. 2007, 129, 2452; k) H.-T. Chang, T. T. Jayanth,
C.-H. Cheng, J. Am. Chem. Soc. 2007, 129, 4166; l) C. S. Lꢁpez,
O. N. Faza, K. S. Feldman, M. R. Iyer, D. K. Hester II, J. Am.
Chem. Soc. 2007, 129, 7638; m) Z. Gu, X. Wang, W. Shu, S. Ma, J.
Am. Chem. Soc. 2007, 129, 10948.
[3] B. B. Lohray, V. Bhushan in Comprehensive Heterocyclic
Chemistry II, Vol. 1b (Eds.: A. R. Katritzky, C. W. Rees, E. F.
V Scriven), Pergamon, NewYork, 1996, p. 911.
[9] a) S. Ma, Z. Shi, J. Org. Chem. 1998, 63, 6387; b) S. Ma, D. Duan,
Z. Shi, Org. Lett. 2000, 2, 1419; c) S. Ma, H. Xie, Org. Lett. 2000,
2, 3801; d) S. Ma, H. Xie, J. Org. Chem. 2002, 67, 6575; e) S. Ma,
S. Zhao, J. Am. Chem. Soc. 1999, 121, 7943; f) S. Ma, W. Gao,
Tetrahedron Lett. 2000, 41, 8933; g) S. Ma, W. Gao, J. Org. Chem.
2002, 67, 6104; h) S. Ma, J. Zhang, Chem. Commun. 2000, 117;
i) S. Ma, L. Li, Org. Lett. 2000, 2, 941; j) S. Ma, S. Zhao, Org. Lett.
2000, 2, 2495; k) S. Ma, N. Jiao, S. Zhao, H. Hou, J. Org. Chem.
2002, 67, 2837; l) S. Ma, N. Jiao, Q. Yang, Z. Zheng, J. Org. Chem.
2004, 69, 6463.
[10] F. P. J. T. Rutjes, K. C. M. F. Tjen, L. B. Wolf, W. F. J. Karstens,
H. E. Schoemaker, H. Hiemstra, Org. Lett. 1999, 1, 717.
[11] a) H. Ohno, M. Anzai, A. Toda, S. Ohishi, N. Fujii, T. Tanaka, Y.
Takemoto, T. Ibuka, J. Org. Chem. 2001, 66, 4904; b) M. Anzai,
A. Toda, H. Ohno, Y. Takemoto, N. Fujii, T. Ibuka, Tetrahedron
Lett. 1999, 40, 7393.
[4] a) E. Koerner von Gustorf, D. V. White, B. Kim, D. Hess, J.
Leitich, J. Org. Chem. 1970, 35, 1155; b) J. Firl, S. Sommer,
Tetrahedron Lett. 1970, 11, 1925; c) J. Firl, S. Sommer, Tetrahe-
dron Lett. 1970, 11, 1929; d) J. Firl, S. Sommer, Tetrahedron Lett.
1972, 13, 4713; e) C. A. Seymour, F. D. Greene, J. Am. Chem.
Soc. 1980, 102, 6384; f) J. H. Hall, M. L. Jones, J. Org. Chem.
1983, 48, 822; g) C. C. Cheng, C. A. Seymour, M. A. Petti, F. D.
Greene, J. Org. Chem. 1984, 49, 2910; h) F. Jensen, C. S. Foote, J.
Am. Chem. Soc. 1987, 109, 6376; i) B. Abarca-Gonzalez, R. A.
Jones, M. Medio-Simon, J. Quiliz-Pardo, J. Sepulveda-Arques, E.
Zaballos-Garcia, Synth. Commun. 1990, 20, 321; j) L. A.
Paquette, P. Webber, L. Simpson, Org. Lett. 2003, 5, 177.
[5] a) S. F. Nelsen, V. E. Peacock, G. R. Weisman, M. E. Landis,
J. A. Spencer, J. Am. Chem. Soc. 1978, 100, 2806; b) J. H. Hall,
W. S. Bigard, J. Org. Chem. 1978, 43, 2785.
[6] W. Miao, W. Xu, Z. Zhang, R. Ma, S.-H. Chen, G. Li,
Tetrahedron Lett. 2006, 47, 6835.
[12] S.-K. Kang, T.-G. Baik, A. N. Kulak, Synlett 1999, 324.
[13] a) S. Ma, F. Yu, J. Li, W. Gao, Chem. Eur. J. 2007, 13, 247; b) S.
Ma, W. Gao, Org. Lett. 2002, 4, 2989.
[14] a) O. Mitsunobu, Synthesis 1981, 1; b) O. Mitsunobu, M.
Yamada, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1967, 40, 935.
[15] The spectrum of this unidentified mixture is rather complicated,
thus, the conclusion is not definite.
[16] a) P. CrabbØ, B. Nassim, M.-T. Robert-Lopes, Org. Synth. 1985,
63, 203; b) S. Ma, H. Hou, S. Zhao, G. Wang, Synthesis 2002,
1643.
[17] a) D. Xu, Z. Li, S. Ma, Chem. Eur. J. 2002, 8, 5012; b) D. Xu, Z.
Li, S. Ma, Tetrahedron: Asymmetry 2003, 14, 3657; c) D. Xu, Z.
Li, S. Ma, Tetrahedron Lett. 2003, 44, 6343.
[7] For recent reviews on Pd-catalyzed cyclization of allenes with
organic halides, see: a) S. Ma, Acc. Chem. Res. 2003, 36, 701;
b) Modern Allene Chemistry, Vol. 2 (Eds.: N. Krause, A. S. K.
Hashmi), Wiley-VCH, Weinheim, 2004; c) S. Ma in Topics in
Organometallic Chemistry (Ed.: J. Tsuji), Springer, Berlin, 2005,
p. 183; d) R. Zimmer, C. U. Dinesh, E. Nandanan, F. A. Khan,
Chem. Rev. 2000, 100, 3067; e) R. W. Bates, V. Satcharoen,
Chem. Soc. Rev. 2002, 31, 12; f) Y. Yamamoto, U. Radhak-
rishnan, Chem. Soc. Rev. 1999, 28, 199.
[8] For some recent typical reactions of allenes, see: a) J. D. Sieber,
J. P. Morken, J. Am. Chem. Soc. 2006, 128, 74; b) P. H. Lee, K.
Lee, Y. Kang, J. Am. Chem. Soc. 2006, 128, 1139; c) S. Ma, Z. Gu,
J. Am. Chem. Soc. 2006, 128, 4942; d) B. M. Trost, J. Xie, J. Am.
Chem. Soc. 2006, 128, 6044; e) Z. Zhang, C. Liu, R. E. Kinder, X.
Han, H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128,
9066; f) J. E. Wilson, G. C. Fu, Angew. Chem. 2006, 118, 1454;
[18] a) D. Lucet, T. L. Gall, C. Mioskowski, Angew. Chem. 1998, 110,
2724; Angew. Chem. Int. Ed. 1998, 37, 2580; b) S. R. S. Saiba-
bu Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des. 2006, 67,
101.
Angew. Chem. Int. Ed. 2008, 47, 4581 –4583
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4583