Phosphine-triggered tandem annulation between Morita-Baylis-Hillman carbonates and dinucleophiles: Facile syntheses of oxazepanes, thiazepanes, and diazepanes

Article abstract of DOI:10.1021/ol302696e

A new phosphine-triggered tandem [3 + 4] annulation reaction between Morita-Baylis-Hillman carbonates and 1,4-diheteroatom dinucleophiles has been developed, which provides a facile synthetic method for saturated seven-membered 1,4-heterocycles such as 1,4-oxazepanes, 1,4-thiazepanes, and 1,4-diazepanes. Mechanistic investigation implies that this reaction takes place through a phosphine-catalyzed allylic alkylation followed by a general base-catalyzed intramolecular Michael cyclization.

Full text of DOI:10.1021/ol302696e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Phosphine-Triggered Tandem Annulation
between MoritaꢀBaylisꢀHillman
Carbonates and Dinucleophiles:
Facile Syntheses of Oxazepanes,
Thiazepanes, and Diazepanes
Rong Zhou, Jianfang Wang, Chong Duan, and Zhengjie He*
The State Key Laboratory of Elemento-Organic Chemistry and Department of
Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, P.R. China
zhengjiehe@nankai.edu.cn
Received September 28, 2012
ABSTRACT
A new phosphine-triggered tandem [3 þ 4] annulation reaction between MoritaꢀBaylisꢀHillman carbonates and 1,4-diheteroatom dinucleophiles
has been developed, which provides a facile synthetic method for saturated seven-membered 1,4-heterocycles such as 1,4-oxazepanes, 1,4-
thiazepanes, and 1,4-diazepanes. Mechanistic investigation implies that this reaction takes place through a phosphine-catalyzed allylic alkylation
followed by a general base-catalyzed intramolecular Michael cyclization.
Saturated seven-membered 1,4-diheteroatom rings, such
as 1,4-oxazepanes,1 1,4-thiazepanes,2 and 1,4-diazepanes,3
are frequently occurring substructures in natural and phar-
maceutical compounds.4 Syntheses of these biologically
important frameworks are, however, somewhat challenging
because the direct ring closures to medium-sized hetero-
cycles are often slow and hampered by unfavorable
enthalpies and entropies of the reactions.5 Although
several methods are available in the literature, syntheses
of these 1,4-heterocycles are often troubled with either
tedious manipulation or harsh conditions.6 New and effi-
cient synthetic approaches are therefore highly desirable.
Nucleophilic phosphine catalysis nowadays emerges as
a rapidly growing area of research interest and has pro-
vided a reliable platform for efficient assembly of cyclic
(1) (a) Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 45, 8333.
(b) Grinsteiner, T. J.; Kishi, Y. Tetrahedron Lett. 1994, 45, 8337.
(c) Koehn, F. E.; McConnelly, O. J.; Longley, R. E.; Sennett, S. H.;
Reed, J. K. J. Med. Chem. 1994, 37, 3181. (d) Audouze, K.; Nielsen,
E. O.; Peters, D. J. Med. Chem. 2004, 47, 3089.
(2) Moormann, A. E.; Metz, S.; Toth, M. V.; Moore, W. M.; Jerome,
G.; Kornmeier, C.; Manning, P.; Hansen, D. W.; Pitzele, B. S.; Webber,
R. K. Bioorg. Med. Chem. Lett. 2001, 11, 2651.
(3) (a) Wattanasin, S.; Albert, R.; Ehrhardt, C.; Roche, D.; Sabio,
M.; Hommel, U.; Welzenbach, K.; Weitz-Schmidt, G. Bioorg. Med.
Chem. Lett. 2003, 13, 499. (b) Wattanasin, S.; Kallen, J.; Myers, S.; Guo,
Q.; Sabio, M.; Ehrhardt, C.; Albert, R.; Hommel, U.; Weckbecker, G.;
Welzenbach, K.; Weitz-Schmidt, G. Bioorg. Med. Chem. Lett. 2005, 15,
1217. (c) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. J. Org.
Chem. 2009, 74, 5652. (d) Riether, D.; Wu, L.; Cirillo, P. F.; Berry, A.;
Walker, E. R.; Ermann, M.; Noya-Marino, B.; Jenkins, J. E.; Albaugh,
(4) (a) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131.
(b) Bremner, J. B.; Samosorn, S. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Joule, J. A., Eds.; Elsevier: Amsterdam, 2008; Vol. 19,
Chapter 7.
(5) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T.
J. Am. Chem. Soc. 2004, 126, 8744.
(6) (a) Clark, S. M.; Osborn, H. M. I. Tetrahedron: Asymmetry 2004,
15, 3643. (b) Shankaran, K.; Donnelly., K. L.; Shah, S. K.; Caldwell,
C. G.; Chen, P.; Hagmann, W. K.; MacCoss, M.; Humes, J. L.;
Pacholok, S. G.; Kelly, T. M.; Grant, S. K.; Wong, K. K. Bioorg.
Med. Chem. Lett. 2004, 14, 5907. (c) Bedurftig, S.; Wunsch, B. Eur. J.
Med. Chem. 2009, 44, 519. (d) Wlodarczyk, N.; Gilleron, P.; Millet, R.;
Houssin, R.; Henichart, J. P. Tetrahedron Lett. 2007, 48, 2583.
(e) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013.
(f) Yan, M.; Mcgarrigle, E.; Aggarwal, V. K. Org. Lett. 2009, 11, 257.
€
D.; Albrecht, C.; Fisher, M.; Gemkow, M. J.; Grbic, H.; Lobbe, S.;
Moller, C.; O’Shea, K.; Sauer, A.; Shih, D.-T.; Thomson, D. S. Bioorg.
€
Med. Chem. Lett. 2011, 21, 2011. (e) Wlodarczyk, N.; Broc-Ryckewaert,
D. L.; Gilleron, P.; Lemoine, A.; Farce, A.; Chavatte, P.; Dubois, J.;
ꢀ
Pommery, N.; Henichart, J.-P.; Furman, C.; Millet, R. J. Med. Chem.
2011, 54, 1178.
r
10.1021/ol302696e
XXXX American Chemical Society

compounds.7 Inthiscontext, phosphine-promotedtandem
annulation reaction between dinucleophiles and unsatu-
rated Michael acceptors represents an attractive protocol
for synthesis of carbo- and heterocycles.8 In 2002, Lu and
co-workers8a first developed a PPh3-catalyzed tandem
umpolung addition/intramolecular Michael cyclization
of electron-deficient allenes or alkynoates with dinucleo-
philes to readily generate functionalized dihydrofurans,
piperazines, morpholines, and diazepanes in a [2 þ n] (n =
3, 4, 5) fashion (Scheme 1, eq a). Interestingly, with similar
substrates, distinct tandem cyclization modes of [1 þ n]
(n = 4, 5) via a double Michael sequence have been
subsequently realized by Kwon8bꢀd through the catalysis
of bisphosphines like 1,3-bis(diphenylphosphino)propane
(DPPP) or electron-rich PMe3, providing easy access to
various five- and six-membered heterocycles (Scheme 1,
eq b). Very recently, an elegant work from Tong’s group8e
unveiled that R-acetoxymethyl allenoates could undergo
phosphine-catalyzed formal [4 þ n] (n = 1, 2) annulations
with dinucleophiles to produce cyclopentenes and tetra-
hydropyridazines (Scheme 1, eq c). All of the above
pioneering studies have unveiled the versatility of the
electron-deficient allenes and alkynes in the phosphine-
catalyzed tandem cyclizations with dinucleophiles.
In the past decade, another class of so-called modified
allylic derivatives such as halides, acetates, and tert-butyl
carbonates, which could be easily prepared from Moritaꢀ
BaylisꢀHillman (MBH) adducts, have proven to be ap-
pealing substrates in an array of phosphine-catalyzed
annulations.9 The pioneering and important reports by
Lu and others have disclosed that such modified allylic
derivatives could be readily used asC3 and C1 synthons in a
number of phosphine-catalyzed [3 þ 2] and [1 þ 4] annu-
lations with various electrophiles including electron-deficient
alkenes and imines. Apart from their uses in the annula-
tion reactions, the allylic derivatives were also reported by
Krische et al. to undertake allylic alkylation reactions
with different nucleophiles under the phosphine catalysis,
producing functionalized products bearing an electrophilic
terminal alkene subunit.10
Scheme 1. Phosphine-Catalyzed Tandem Annulations with
Dinucleophiles
Considering the above diverse reactivity of the allylic
derivatives and the fact that nucleophilic phosphines are
capable of triggering Michael addition reactions between
activated alkenes and pronucleophiles,11 we envisaged that,
under the mediation of phosphines, dinucleophiles and
the modified allylic derivatives such as tert-butyl MBH
carbonates could undertake a tandem allylic alkylationꢀ
intramolecular Michael cyclization process, thereby leading
to new entries for carbo- and heterocycles.12 Following
this strategy, we investigated a phosphine-triggered tandem
[3 þ 4] annulation reaction between MBH carbonates 1 and
1,4-diheteroatom dinucleophiles 2 to generate saturated
seven-membered 1,4-heterocycles (Scheme 1, eq d). Herein
we report the preliminary results.
Enantiopure β-amino alcohol 2a derived from L-valine
was chosen as a dinucleophile to evaluate our proposal.
To our delight, a model reaction of MBH carbonate 1a
(0.6 mmol) and dinucleophile 2a (0.5 mmol) under the
catalysis of PPh3 (20 mol %) in refluxing acetonitrile
produced the expected 1,4-oxazepane 3a in 46% isolated
yield and 7:1 dr after 48 h (Table 1, entry 1). A brief survey
on the model reaction conditions was further carried out to
improve the annulation efficiency.
(7) For leading reviews on phosphine-catalyzed annulations, see: (a)
Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot,
J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ye, L.-W.;
Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Cowen, B. J.;
Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (e) Marinetti, A.; Voituriez,
A. Synlett 2010, 174.
(8) (a) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (b) Sriramurthy,
V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928.
(c) Sriramurthy, V.; Kwon, O. Org. Lett. 2010, 12, 1084. (d) Szeto, J.;
Sriramurthy, V.; Kwon, O. Org. Lett. 2011, 13, 5420. (e) Zhang, Q.;
Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550.
A series of nucleophilic phosphines were examined
(Table 1, entries 1ꢀ10). Triarylphosphines bearing electron-
donating groups on phenyl rings showed relatively better
catalytic activity with P(4-CH3C6H4)3 offering the best yield
of 3a (entry 2). Relatively electron-poor triarylphosphines
such as P(4-FC6H4)3 and P(4-CF3C6H4)3 were, however,
completely ineffective for the annulation reaction. Electron-
richer alkylarylphosphines such as Ph2PMe, PhPMe2, and
tributylphosphine were less effective, only giving 3a in modest
(9) For selected examples of [3 þ 2] annulations, see: (a) Du, Y.; Lu,
X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035. (b) Du, Y.; Feng, J.;
Lu, X. Org. Lett. 2005, 7, 1987. (c) Feng, J.; Lu, X.; Kong, A.; Han, X.
Tetrahedron 2007, 63, 6035. (d) Zheng, S.; Lu, X. Org. Lett. 2008, 10,
4481. (e) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.; Tang, Y. Angew. Chem.,
Int. Ed. 2007, 46, 5951. (f) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett.
2011, 13, 580. (g) Deng, H.-P.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 3348.
(h) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2011,
133, 4672. (i) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int.
Ed. 2011, 50, 7837. For examples of [1 þ 4] annulations, see: (j) Chen, Z.;
Zhang, J. Chem.;Asian J. 2010, 5, 1542. (k) Xie, P.; Huang, Y.; Chen,
R. Org. Lett. 2010, 12, 3768. (l) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He,
Z. J. Org. Chem. 2011, 76, 2374. (m) Zhang, X.-N.; Deng, H.-P.; Huang,
L.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48, 8664.
(11) (a) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem.
Soc. 2003, 125, 8696. (b) Reference 8d.
(12) A sole example of phosphine-catalyzed [3 þ 3] annulation of
MBH carbonates with C,C-dinucleophiles was reported previously.
Zheng, S.; Lu, X. Tetrahedron Lett. 2009, 50, 4532.
(10) For selected examples, see: (a) Cho, C.-W.; Kong, J.-R.;
Krische, M. J. Org. Lett. 2004, 6, 1337. (b) Cho, C.-W.; Krische, M. J.
Angew. Chem., Int. Ed. 2004, 43, 6689. (c) Park, H.; Cho, C.-W.; Krische,
M. J. J. Org. Chem. 2006, 71, 7892. (d) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M.
J. Am. Chem. Soc. 2008, 130, 7202.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Surveying on the Model Reaction Conditionsa
Table 2. Synthesis of 1,4-Heterocycles 3 from Carbonates 1 and
Dinucleophiles 2a
yield of 3a
(%)b, drc
yield of
4a (%)b
entry
phosphine
PPh3
solvent
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
46, 7:1
55, 8:1
44, 7:1
/
/
2
P(4-CH3C6H4)3
P(4-CH3OC6H4)3
P(4-FC6H4)3
P(4-CF3C6H4)3
Ph2PMe
/
entry
E in 1
2
time (h)
yield of 3 (%),b drc
3
/
4
17
1
CO2Bu-t, 1a
CO2Bu-t, 1a
CO2Bu-t, 1a
CO2Bu-t, 1a
CO2Bu-n, 1b
CO2Bu-n, 1b
CO2Et, 1c
CO2Et, 1c
CO2Me, 1d
CN, 1e
2a
2b
2c
2d
2a
2d
2a
2c
2a
2a
2e
2f
48
48
48
48
24
48
36
48
24
48
24
36
36
24
3a, 91, 11:1
3b, 87, 10:1
3c, 70, 5:1
3d, 74
5
/
/
2
6
32, 8:1
24, 7:1
39, 6:1
23, 6:1
24, 10:1
76, 11:1
43, 6:1
40, 8:1
53, 6:1
47, 9:1
91, 11:1
/
3
7
PhPMe2
/
4
8
PBu3
/
5
3e, 72, 14:1
3f, 81
9
DPPE
/
6
10
11
12
13
14
15
16d
(S)-BINAP
39
7
3g, 86, 13:1
3h, 85, 20:1
3i, 80, 20:1
3j, 39, 1.5:1
3k, 94, 7:1
3l, 68
P(4-CH3C6H4)3
P(4-CH3C6H4)3
P(4-CH3C6H4)3
P(4-CH3C6H4)3
P(4-CH3C6H4)3
P(4-CH3C6H4)3
/
8
/
9
CHCl3
14
10d
11
12e
13
14
THF
/
/
/
CO2Et, 1c
CO2Bu-t, 1a
CO2Et, 1c
CO2Et, 1c
toluene
CH2Cl2
2f
3m, 90
a Typical conditions: under a N2 atmosphere, a mixture of 1a (0.6 mmol),
2a (0.5 mmol), and phosphine (0.1 mmol) in solvent (2.0 mL) was stirred
under reflux or at 60 °C for 48 h. b Isolated yield based on 2a. c Determined by
1H NMR assay and referring to the ratio of cis-3a/trans-3a. d Carbonate 1a
(1.0 mmol) was used.
2g
3n, 67
a For details, see Supporting Information. b Isolated yield. c Ratio of
cis-3/trans-3 and determined by 1H NMR assay of the isolated 3. d cis-3j
and trans-3j were separable by column chromatography and obtained in
23% and 16% yields, respectively. e A double allylic alkylation byprod-
cut 4b was isolated in 20% yield.
yields (entries 6ꢀ8). In sharp contrast with Kwon’s results
that bisphosphines are superior catalysts for the tandem
double Michael annulation reaction of alkynoates with
dinucleophiles,8b,c bisphosphines such as DPPE [1,2-bis-
(diphenyphosphino)ethane] and BINAP only delivered
inferior yields of the cyclic product 3a (entries 9, 10), although
BINAP brought about the acyclic N-allylation product 4a in
a substantial yield (entry 10). By choosing P(4-CH3C6H4)3 as
the catalyst, several common solvents were screened (entries
11ꢀ15). Dichloromethane emerged as a preferred solvent,
affording 3a in 76% yield (entry 11). Gratifyingly, the yield of
3a could be further upgraded to 91% by adjusting the molar
ratio of 1a/2a to 2:1 (entry 16). Thus, the preferable condi-
tions for the annulation reaction were established.
Under the optimized conditions, the substrate scope of
the tandem annulation reaction was investigated. A couple
of β-amino alcohols 2 prepared from natural amino acids
were examined with MBH carbonate 1a, and the corre-
sponding 1,4-oxazepanes 3 were readily obtained in good
yields with good diastereoselectivity (cis-3/trans-3 = 5:1ꢀ
11:1) (Table 2, entries 1ꢀ4). MBH carbonates 1with varying
alkyl groups were also tested in the reactions with repre-
sentative β-amino alcohols 2: the change of the alkyl
group did not significantly interfere with the annulation
reaction concerning the yield and stereoselectivity (entries
5ꢀ9). Cyano substituted allylic carbonate 1e was also
effective in the annulation with β-amino alcohol 2a, albeit
giving the cyclic product 3j in modest yield and low
diastereoselectivity (entry 10). Other 1,4-dinucleophiles
than β-amino alcohols were also found to be effective in
this tandem annulation reaction. Under standard conditions,
β-amino thiol 2e and MBH carbonate 1c readily afforded
1,4-thiazepane 3k in 94% yield and 7:1 dr (entry 11).
Furthermore, both aliphatic and aromatic 1,2-diamines
2f and 2g were good dinucleophiles in the annulation re-
action, furnishing the corresponding 1,4-diazepanes 3lꢀm
and benzo[b][1,4]diazepine 3n in good yields, respectively
(entries 12ꢀ14). Both [1,4]diazepanes and benzo[1,4]dia-
zepines are privileged skeletons in the biologically active
molecules and drugs.13
The structures and stereochemistry of the annulation
products 3 were identified by 1H, 13C NMR and HRMS-
ESI measurements, as well as by HMQC, NOESY, and
X-ray crystallographic analyses for representative com-
pounds (for details, see Supporting Information).14
To glean mechanistic clues about this tandem annula-
tion, the following experiments were deliberately conducted
(13) (a) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65.
(b) Lee, S.-C.; Park, S. B. Chem. Commun. 2007, 3714 and references
cited therein. (c) Attanasi, O. A.; Crecentini, L. D.; Favi, G.; Mantellini,
F.; Nicolini, S. J. Org. Chem. 2011, 76, 8320. (d) Chen, X.; Zheng, Y.;
Shu, C.; Yuan, W.; Liu, B.; Zhang, X. J. Org. Chem. 2011, 76, 9109.
(14) A similar NMR method was applied to determine the stereo-
chemistry of seven- and eight-membered heterocycles. See ref 5.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Mechanistic Experiments
Scheme 3. Proposed Mechanism for the Phosphine-Triggered
Tandem Annulation Reaction
(Scheme 2). The allylic alkylation product 4a, which was
collected from the model reaction experiments (Table 1),
was first subjected to the standard phosphine-triggered
annulation reaction conditions, the expected cyclization
product 3a was uneventfully obtained, but in a fair yield
(Scheme 2, eq e). Interestingly, when equimolar MBH
carbonate 1c was introduced into the above reaction
under otherwise identical conditions, the yield of 3a was
significantly increased to 85% (Scheme 2, eq f). This
result clearly confirms that addition of the carbonate
1c facilitates the phosphine-triggered intramolecular
Michael cyclization of 4a. Furthermore, when acyclic 4a
was treated under the general base catalysis of t-BuOK,
the Michael cyclization product 3a was also smoothly
obtained in 84% yield with comparable stereoselectivity
(eq g). The above results strongly imply that the phos-
phine-mediated Michael cyclization of 4a is most likely a
general base-catalyzed process. The in situ generated tert-
butoxide anion from nucleophilic attack of the phosphine
at the allylic carbonate subunit of 4a or carbonate 1c acts
as the base catalyst.8d,9f,10a Extra addition of carbonate 1c
guaranteed a sufficient supply of the base tert-butoxide
anion for the Michael cyclization of 4a so that the yield of
3a was significantly improved (eq f). The yield increase of
3a in the model reaction by increasing the loading of
carbonate 1a could be well interpreted by this assumption
(Table 1, entry 14).
intermediate 4 and regenerate the catalyst phosphine.
Under the influence of the in situ generated tert-butoxide
anion base, intermediate 4 finally undertakes a 7-endo-
trig cyclization to accomplish the tandem assembly of
cyclic product 3.
In summary, a new phosphine-triggered tandem [3 þ 4]
annulation reaction between MoritaꢀBaylisꢀHillman
carbonates 1 and 1,4-diheteroatom dinucleophiles 2 has
been developed, which provides a facile synthetic method
for saturated seven-membered 1,4-heterocycles such as
1,4-oxazepanes, 1,4-thiazepanes, and 1,4-diazepanes. Based
on mechanistic investigations in this study and closely
related reports8d,10a in the literature, this tandem an-
nulation reaction is supposed to proceed through a
phosphine-catalyzed allylic alkylation followed by a gen-
eral base-promoted intramolecular Michael cyclization.
With regard to other established phosphine-catalyzed
tandem annulations of electron-deficient allenes oralkynes
with dinucleophiles, this reaction particularly provides a
complementary route to medium-sized heterocycles. Our
future efforts will be directed toward further expanding the
reactionscopeand exploringitsapplication inthe synthesis
of biologically important compounds.
Acknowledgment. Financial support from National
Natural Science Foundation of China (Grant Nos.
21072100; 21121002; 21272119) is gratefully acknowledged.
Based on above mechanistic insights and previous re-
ports on the phosphine-triggered allylic alkylation10a and
Michael cyclization,8d a proposed mechanism was depicted
in Scheme 3 to account for the formation of heterocycles 3.
Initially, nucleophilic attack of the catalyst phosphine at
allylic carbonate 1 in an SN20 fashion results in a phos-
phonium tert-butoxide 5, which in turn deprotonates
dinucleophile 2 to bring about an ion pair of phospho-
nium-nucleophile anion 6. Ion pair 6 then undergoes
another SN20 substitution to afford allylic alkylation
Supporting Information Available. Experimental de-
tails, characterization data and NMR spectra for new
compounds 3 and 4, and the X-ray crystallographic data
(CIF files) for 3n and 4b. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX